CZ187493A3 - Process for preparing carbapenem and penem compounds and novel compounds comprised in said process - Google Patents

Abstract

Penem and carbapenem compounds having a group of formula -SA are prepared from a corresponding compound having a substituted thio, sulphinyl or sulphonyl group at this position by reaction with a compound ASH (where A is various organic groups) in the presence of a salt of a metal of Group II or III of the Periodic Table.

Description

Technical Field of the Invention

The present invention relates to novel processes for the preparation of groups of carbapenem and penem compounds useful as antibiotics. The invention also relates to groups of novel intermediates used in this process.

BACKGROUND OF THE INVENTION i

Penam and cephem antibiotics have been known for many years and have shown considerable value in the control and prevention of infectious diseases. Currently, penem and carbapenam antibiotics have been developed and found to be very useful. The penem and carbapenem compounds have a common basic structure, which can be represented by the formula A:

(A) n '

• 3

where

Z represents a sulfur atom or a group of formula GH _{2 #} which may optionally be substituted by an alkyl or alkoxy group.

Compounds in which Z represents a sulfur atom are the penem ,, while compounds in which Z represents a group of formula> CH ₂ 3 ^SOU carbapenem compound. In accordance with the recommendations of the International Union of Pure and Applied Chemietry (IUPAC), the compounds described herein are named semisystematically using penem and carbapenem as the starting compound. For the avoidance of doubt, the above formula A also has the corresponding numbering in the peripheral numbering system used herein to describe the compounds.

Several compounds having a thiol group attached to the 2nd position of a penem or carbapenem compound are known and are considered valuable antibiotics.

-ί

Many such compounds are synthetically produced. In particular, the 1β-methylcarbapenem derivatives which are currently of considerable interest in this field must be produced synthetically, since no microorganism has been found. to rule them out. An excellent method of synthesizing such compounds, overcoming many of the drawbacks of the prior art, is described in Japanese Patent Application Ser.

Hei 1-25730 and involves oxidizing the sulfur atom on carbapenem at the 2-position relative to the S-oxide (i.e. sulfinyl or sulfonyl group) and then replacing the resulting sulfinyl or sulfonyl group with the desired mercapto group, for example as shown in the following reaction:

HS

CONH _;

PNZ ►

When this reaction is carried out by conventional methods in which organic bases are used, in many cases the sulfamic acid generated by the substitution reaction induces the production of various kinds of by-products, resulting in a low reaction yield. For example, the yield of the addition elimination reaction in the above reaction scheme is reported as 22¾ in Kokai Japanese Patent No. Hei 1-25780.

It has now surprisingly been found that if the reaction is carried out in the presence of Group II or III metal salts of the Periodic Table of the Elements, instead of organic bases, yields can be greatly improved and yields of 40 to 30% or more can be achieved (sometimes over 90%), instead of the yields obtainable by prior art procedures, which at best are about 20%.

*, ř d

; ··

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of 2-substituted thio derivatives.

i · ./W '.-d - · parts 5

Another and more specific object of the invention is a process for making these compounds allowing them to be obtained in high yields. Other objects and advantages will become apparent throughout the description of the invention.

In general terms, the invention relates to a process for preparing a compound of formula I:

R ² R ³

AND-'*

X. ✓SA 'COOR ¹ (I)

where it represents a hydrogen atom or a carboxy protecting group,

3. .

R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 0 Y carbon atoms, and groups of the formula

.i i

• 1

-and

AU • iř

>, S>

where

R is hydrogen or methyl and.

R represents a hydrogen atom or a hydroxy protecting group, or 23 g

R and R together form skuoinu formula = C (CH,) CH _about 0R, in which ~ SW

R is as defined above, * 7 7

X is a sulfur atom or a group of formula CHR, wherein R is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms, and

A represents an alkyl group having from 1 to 6 carbon atoms and which is unsubstituted or substituted by one or two substituents selected from the group consisting of the substituents A as defined below, an aryl group as defined below, an aralkyl group in which an alkyl group having

 i · í

'3 ·?

is substituted by at least one aryl group as defined below, a heterocyclic group having from 3 to 10 ring atoms, at least one of said atoms being a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms said group being unsubstituted or substituted by at least one substituent selected from the group consisting of B substituents on carbon, substituents on nitrogen heteroatoms and oxygen atoms to form a sulfinyl or sulfonyl group on sulfur heteroatoms, all as defined below, fused heterocyclic a group in which the heterocyclic group as defined above is fused with an aryl group as defined below, or an alkyl group having from 1 to 6 carbon atoms and which is substituted with at least one substituent selected from the group consisting of heterocyclic groups and the above defined fused h said aryl groups are aromatic carbocyclic groups having from 6 to 14 carbon ring atoms and are unsubstituted or substituted by at least one substituent selected from the group consisting of substituents C as defined below, said A substituents being selected from the group consisting of hydroxy, protected hydroxy groups, amino groups, protected amino groups, groups of the formula -C (= Nr 1 G JNrUr 4), wherein _R 10 -11 12.

, k and R j are independently selected from the group consisting of hydrogen atoms, amino protecting groups and alkyl groups having from 1 to 6 carbon atoms, or R and R together are a group of the formula

- (CH_) -, wherein n is an integer from 2 to 6, or R ⁸ and 11 ^zn

R skuninu together represent the formula - (CH ~) wherein p is 2 or p 3, and groups of formula -NR ¹³ C (= NR ¹⁴⁾ R ¹³ wherein R \ 3 and R ³ are independently selected from the group consisting of hydrogen atoms, protective amino groups, and alkyl groups having from 1 to 6 carbon atoms, and

R ( ³⁾ is hydrogen, alkyl having from 1 to 6 carbon atoms, amino or protected amino, or any two of R ( ³⁾ , R ( ⁴⁾ and R ( ³⁾ together are - (CH-) wherein p is 2 or 3, p ^J said substituents B are selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, hydroxy groups, halogen atoms, cyano groups, nitro groups, alkoxycarbonyl groups having 2 to 6 carbon atoms ,

And ¹ carboxy groups, to form oxygen atoms, to form a carbonyl group with a ring carbon atom, a cycloalkyl group having from 3 to 7 ring carbon atoms, alkoxy groups in which the alkoxy and alkyl moieties have from 1 to 5 carbon atoms; up to 6 carbon atoms, alkoxycarbonylalkyl groups in which the alkoxy and alkyl moieties have from 1 to 6 carbon atoms, cyanoalkyl groups in which the alkyl moiety has from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkanoyloxy groups having from (C 1 -C 6), azido, (C 1 -C 6) alkylthio, (C 1 -C 6) alkylsulphinyl, (C 1 -C 6) alkylsulphonyl,

Groups of formula -NR κ and groups of formula -CONR R, where

9

R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having from 1 to 6 carbon atoms and 8-9 phenyl groups, or R and R together are - (CH_) -O- (CH- ) - wherein q and s are independently 2 qr 2 s selected from the group consisting of 0 and integers from 1 to 5 and r being 0 or 1, provided that (q + s) is an integer at least 2, and * groups of formulas BI , B-II, B-IV, BV-B,

B-VII, B-VIII, and B-IX

(BI)

· '♦

4 “*

ve which and is 1, 2 or 3, b is 0, 1 ' or 2, C is 0 or 1, d is 0, 1 or 2, E is 0, 1 or 2, F is 0, 1 or 2, G is .0, 1 or 2, h is 0, 1 or 2, R ²⁰ means atom hydrogen,

Τ _4

pin, a group of formula -COR, wherein

R represents an alkyl group having from 1 to 6 carbon atoms or a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of substituents A,

17 a group of formula C - (= NR) R ', wherein

1617 * '*

R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, amino groups, protected amino groups and amino protecting groups, -Δα

an unsubstituted alkyl group having from 1 d of 6 carbon atoms or a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted with at least one substituent selected from the group consisting of substituents D below,

22nd

R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 atoms

----,

Λ e

'1' I

carbon, hydroxy and protected hydroxy,. ,

R represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,

29

R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, amino protecting groups, amino groups, protected amino groups, and groups of formula -C (= NR? R) R? ⁷ , wherein R? ® and R ^ ⁷ are as defined above,

R (5) is hydrogen, alkyl having from 1 to 6 carbon atoms or: substituted alkyl having from 1 to 6 carbon atoms and substituted with at least one substituent selected from the group consisting of hydroxy and protected hydroxy groups,

R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an amino protecting group,

R represents a hydrogen atom, an alkyl group having from 1 to 28, 29 to 6 carbon atoms, or a group of the formula -NR R7;

2Q 29 which R and R are as defined above,

E represents an imidazolyl group or a triazolyl group,

W represents an aromatic heterocyclic group having from 5 to 8 ring atoms, of which from 1 to 4 are nitrogen atoms, said heterocyclic group being unsubstituted or substituted by at least one alkyl group having from 1 to 6 carbon atoms,

?. · J · * V? .

fy

OF

3

Q, Q, Q and Q are independently selected from the group consisting of groups of formula> CH and> N, said substituents B ^first are selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, amino protecting groups, groups of the formula

-C (= Nr 1θ) r 1, where R 1a are as defined above, amino protecting groups and groups of formula 1819 18 19

-CONR R, wherein R and R are independently selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms and carboxyl acyl groups, said C substituents being selected from the group consisting of C1-6 alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, alkoxycarbonyl groups having from 2 to 7 carbon atoms, groups -CONR R, where R and R are as defined above, cyano, hydroxy and nitro groups, said substituents D being selected from the group of consisting of hydroxy, protected hydroxy, carboxy, protected carboxy, cyano, alkoxy of 1 to 6 carbon atoms, alkylsulfonyl groups of 1 to 6 carbon atoms, -NHCOR, -NR ²⁴ R ²⁵ , -CONR ²⁴ R ²⁵ or -OCONR ²⁴ R ²⁵ , wherein R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 6 carbon atoms, and their pharmaceutically acceptable salts and esters, by reacting a compound of formula II

. , ¾

)

-Λ * ί

3.

wherein R, R, R, and X are as defined above, k is 1 or 2a.

R stands for:

an alkyl group having from 1 to 6 carbon atoms which is unsubstituted or substituted by at least one substituent selected from the following substituents E, and an alkenyl group having from 2 to 6 carbon atoms which is unsubstituted or substituted by at least one a substituent selected from the group of the following substituents E, an aryl group as defined above, an aralkyl group in which an alkyl group having from 1 to 6 carbon atoms is substituted by at least one aryl group as defined above, a cycloalkyl group having from 3 to Which is unsubstituted or which is substituted by at least one substituent selected from the group consisting of the above-mentioned substituents C, an aromatic heterocyclic group having from 5 to 7 ring atoms, in the aromatic ring, with at least one of these atoms is a heteroatom selected from the group consisting of he nitrogen, oxygen and sulfur teratoms, said group being unsubstituted or substituted by at least one substituent selected from the group of the above substituents C, a linked heterocyclic group in which the aromatic heterocyclic group is as defined above, bonded to an aryl group as defined above, or fř ί

an alkyl group having from 1 to 6 carbon atoms which is substituted by at least one substituent selected from the group consisting of heterocyclic groups and linked by the above-mentioned heterocyclic groups, and said E substituents are selected from the group consisting of hydroxyl-protected hydroxy groups, amino and protected amino groups, ...... 'with a compound of formula III'

ASH (WHERE A is as hereinbefore defined and, if desired, removes any protecting group in which the improvement is that the reaction of the compound of formula II and the compound of formula III is carried out in the presence of a Group II or III metal salt element tables., <,

Certain compounds of formula II used as starting materials in the above reaction are novel compounds and also form part of the invention. These novel compounds are compounds of formula IV

'ί' ϊί'ίβ ^,,>>>>>> i «-« vlwiVříJ> order ί

. , -, ί & W where it is defined above,,,

R is hydrogen or a hydroxy protecting group; f

R represents an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, | a halogen atom, an aryl group as defined above, or an aryloxy group in which the aryl moiety has the meaning defined above,

R is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, hydroxy, halogen, cyano, nitro or -NR R,

9. wherein R and R are as defined above,

46. ,

R and R are independently selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms and aryl groups as defined above, or "45-46"

R and R together represent a group of formula

- (CH_) -O- (CH-) -, wherein 2 q 2 s q as are independently selected from the group consisting of <3 of 0 and integers from 1 to 5 and * r is 0 or 1,

Y represents an oxygen atom or a sulfur atom, and j is 0, 1 or 2, and pharmaceutically acceptable salts and esters thereof.

In compounds of formula X, II and IV, wherein R ¹ is a carboxy-protecting group, it may be a group,

'5

- '* ·' ϊί

9 * ·

Ii commonly used in the synthesis of beta-lactam antibiotics, and there are no particular limitations on the compounds of formulas II and IV which are intermediates, and the desired compounds of formula I which may be used for therapeutic purposes require: care for the selection of the protecting group, if any. More preferably, in the case of compounds of formula I, κ represents a hydrogen atom or an ester group, as will be described in more detail below. Examples of such protecting groups include:

lower alkyl groups having from 1 to 6, preferably from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,

2-methylbutyl, 1-ethylpropyl, 4-methylpentyl,

3-methylpentyl, 2-methylpentyl, 1-methylpentyl,

3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups, of which preferably such alkyl groups having from 1 to 4 carbon atoms, methyl, ethyl and tert-butyl groups, aralkyl groups, preferably alkyl groups having from 1 to 4, preferably from 1 to 3, more preferably 1 or 2, and most preferably And which are substituted with at least one (more preferably 1, 2 or 3) aryl groups as defined above, such as benzyl, diphenylmethyl, triphenylmethyl, 4-nitrobenzyl, 2-nitrobenzyl, 1-naphthylmethyl, alpha-methylbenzyl, alpha alpha-dimethylbenzyl, 1-phenylethyl, phenethyl (i.e. 2-phenylethyl). 3-phenylpropyl and 4-phenylbutyl groups of which benzyl, diphenylmethyl,

4-nitrobenzyl and 2-nitrobenzyl groups,

Ί alkenyl groups having 2 to 6, preferably 3 or 4, carbon atoms and optionally substituted by one or more halogen atoms, such as vinyl, allyl, 2-chlorallyl or 2-methylallyl groups, haloalkyl groups having 1 to 6, preferably 1 to 6 carbon atoms; 4 ato- g.

carbon such as trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluorine, methyl, chloromethyl, bromomethyl, iodomethyl,

2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromethyl, 3-chloropropyl, 3,3,3-trichloropropyl, per • f luorethyl, 4-fluorobutyl, 5-bromopentyl, 6-chloro-hexyl and 6,6,6-trifluorohexyl groups, preferably 2,2,2-trichloroethyl or 2,2,2-tribromethyl and trisubstituted silylethyl groups, all of which; three or two or one of the substituents are alkyl groups having from 1 to 5, preferably 1 to 4 carbon atoms and none, one or two of the substituents being aryl groups, as | have been defined above, but preferably phenyl or substituted phenyl groups, preferably 1- or 2- / tri (lower alkyl) silyl / ethyl groups, such as 2- (trimethylsilyl) ethyl; 2- (triethylsilyl) ethyl, 2- (isopropyldimethylsilyl) ^? ethyl, 2- (t-butyldimethylsilyl) ethyl, 2- (methyl-).

, ¹ »?

diisopropylsilyl) ethyl, 2- (methyldi-tert-butylsilyl) ethyl and 2- (triisopropylsilyl) ethyl groups and 1- or 2Sm-2

M - / tri (lower alkyl) silyl / ethyl groups in which one or two of the alkyl groups have been replaced by aryl groups such as 2- (diphenylmethylsilyl) ethyl groups, 2- (di phenylbutylsilyl) ether, 2- (diphenyl-tert-butyl) groups butylsilyl-ethyl, 2- (diphenylisopropylsilyl) ethyl and 2- (phenyldiisopropylsilyl) ethyl groups, in particular 2- (trimethyl-4-silyl) ethyl groups;

acyloxyalkyl groups in which the acyl moiety is an alkanoyl group having 1 to 6, preferably 1 to 5 carbon atoms and the alkyl moiety having 1 to 6, preferably 1 or 2 carbon atoms such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl , 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-pivaloyloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-pivaloyloxybutyl, 1-acylethoxybutyl, 1-acylethoxybutyl acetoxypentyl and 1-acetoxyhexyl groups, preferably acetoxymethyl, pivaloyloxymethyl and 1-acetoxyethyl groups, alkoxycarbonyloxyalkyl groups in which the alkoxy and alkyl moieties each have 1 to 6, preferably 1 to 4 carbon atoms, such as ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) - , 1- (isopropoxycarbonyloxy) ethyl and tert-butoxy] carbonyloxymethyl groups; / cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl moiety has from 3 to 7, preferably 5 or 6, carbon atoms in _the ring and may be unsubstituted or substituted by at least one substituent selected from the group of the above and below examples of C but especially from an alkyl group having 1 to 6, preferably 1 to 4, and more preferably 1 or 2 carbon atoms, and an alkyl moiety having 1 to 6, more preferably 1 to 4, and more preferably 1 or 2 carbon atoms, such as 1- (cyclohexyloxycarbonyloxy) ethyl and (1-methylcyclohexyl) oxycarbonyloxymethyl groups,

- \ | (5-alkyl or 5-aryl-2-oxo-1,3-dioxolen-4-yl) methyl groups wherein the alkyl moiety has 1 to 4, preferably 1 or 2 carbon atoms and the aryl moiety is as defined above but is preferably a phenyl group such as (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl and (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl groups, and

Go

-¾

Λ <

A 3-phthalidyl group.

- 'žft

TO

Of the above acyloxyalkyl groups, alkoxycarbonyloxyalkyl groups, cycloalkoxycarbonyloxyalkyl groups,

(5-alkyl or 5-aryl-2-oxo-1,3-dioxolen-4-yl) methyl groups and 3-phthalidyl groups are capable of hydrolysis in vivo and are therefore particularly advantageous in particular where they are retained in the final product for therapeutic use.

In case that R, R ^J, or R ⁴ represents an alkyl group, this may be a straight or branched alkyl group having from 1 to 6, preferably 1 to 4 carbon atoms, and examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec.butyl, tert.butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl,

4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3- dimethylbutyl, 2-ethylbutyl, hexyl and ixohexyl groups. Of these, preference is given to such alkyl groups having from 1 to 4 carbon atoms, preferably methyl;

ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups, and most preferably »-% methyl and ethyl groups.

3,

Where R or R represents a group of the formula

CH

-C - R ⁵ in ** '·· $ •' 7 * ty

OR ⁸ and R ⁸ represent a hydroxy protecting group / the hydroxy protecting group may be selected from any protecting group known in the art for use with beta-lactam antibiotics. Examples of such groups are given by TW Green in Protective Groups in Organic Synthesis, John Wiley and Sons, and JFW McOmie in Protective Groups in Organic Chemistry (Plenum Press), the disclosures of which are incorporated herein by reference. More specifically, such preferred protecting groups include:

substituted silyl groups in which the silyl group has up to dp 3 and preferably 3, substituents selected from alkyl groups having from 1 to 6 carbon atoms and phenyl groups which are unsubstituted or have at least one substituent selected from the aforementioned substituents C below examples, for example trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl, aralkyl groups which are preferably alkyl groups having from 1 to 4, preferably from 1 to 3, more preferably 1 or 2, and most preferably 1 carbon atom, and are substituted with at least one (more preferably 1, 2 or 3) aryl groups as defined above such as benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-nitrobenzyl, 1-naphthylmethyl, alpha-methylbenzyl, alpha, alpha-dimethylbenzyl, 1-phenylethyl, phenethyl, 3-phenylpropyl and 4-phenylethyl; nylbutyl groups in which benzyl, 4-methoxybenzyl, 4-nitrobenzyl and 2-nitrobenzyl groups, oxycarbonyl groups, including:

aralkyloxycarbonyl groups in which the aralkyl moiety may have the meaning given above and the examples mentioned, preferably benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and benzhydryloxycarbonyl groups, alkenyloxycarbonyl groups, in which the alkenyl moiety preferably has from 2 to 6 carbon atoms, it may be unsubstituted or it may be substituted by at least one (preferably from 1 to 3, more preferably 1) halogen atom such as allyloxycarbonyl, 2-chlorallyloxycarbonyl and 2-methylallyloxycarbonyl and 2-methylallyloxycarbonyl groups, alkoxycarbonyl groups having a total of from 2 to 2 7. carbon atoms, that is, in which the alkyl moiety has. from 1 to 6 carbon atoms and may be any of the above alkyl groups, and which may be unsubstituted or may be substituted by at least one (preferably from 1 to 3, more preferably 1 or 3) halogen atoms such as 2,2,2 -tribromethoxycarbonyl and t-butoxycarbonyl groups, and substituted silylalkoxycarbonyl groups in which the alkoxycarbonyl moiety is as defined above and the substituted silyl moiety is as defined above and exemplified as 2- (trimethylsilyl) ethoxycarbonyl; , ether groups, including:

% of oxygen-containing heterocyclic groups, e.g. substituted and unsubstituted tetrahydropyrasyl and tetrahydrofuranyl groups such as tetrag hydropyranyl,

21 alkoxyalkyl groups in which the alkoxy and alkyl moieties each have from 1 to 6, preferably from 1 to 4, and more preferably 1 or 2 carbon atoms, such as methoxymethyl and 1-ethoxyethyl groups, of substituted silylalkoxyalkyl groups in which the alkoxyalkyl moiety has the above the defined and exemplified meaning and substituted silyl moiety also has the above defined and exemplified meaning, such as 2- (trimethylsilyl) ethoxymethyl, and alkanoyl and haloalkanoyl groups having from 1 to 6 carbon atoms (2 to 6 in the case of haloalkanoyl groups) ) such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isobutyryl, valeryl, isovaleryl, pivaloyl and chloroacetyl groups.

When R is an alkyl group having from 1 to 6 carbon atoms, it may be a straight or branched chain group and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,

3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and ixohexyl groups. Of these, preference is given to such alkyl groups having from 1 to 4 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl and sec-butyl, and most preferably methyl. _K If R? represents an alkoxy group having from 1 to 6 carbon atoms, which may be a straight or branched chain radical;

-i i

The branched chain and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy,

2-methylbutoxy-, 1-ethylpropoxy-, 4-methylpentyloxy-, 3-methylpentyloxy-, 2-methylpentyloxy-, 1-methylpentyloxy-,

3,3-dimethylbutoxy-, 2,2-dimethylbutoxy-, 1,1-dimethylbutoxy-, 1,2-dimethylbutoxy-, Γ, 3-dimethylbutoxy-, 2,3-dimethylbutoxy-, 2-ethylbutoxy-, hexyloxy and isohexyloxy groups. Of these, alkoxy groups having from 1 to 4 carbon atoms are preferred, preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy and sec-butoxy groups, and most preferably methoxy.

When A is an alkyl group, it may be a straight or branched chain group having from 1 to 6, preferably from 1 to 4 carbon atoms, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl tert-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl; 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,

1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups. Of these, alkyl groups having from 1 to 4 carbon atoms are preferred, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups, and most preferably methyl and ethyl groups.

In the case where A represents a substituted alkyl group, the alkyl moiety may be any of the unsubstituted groups defined above, and the examples thereof and the substituents are ^- selected from substituents A, including:

: ¾

Hydroxy groups, protected hydroxy groups as defined above 6 and examples given in relation to R, amino, protected amino groups in which the protecting group may be selected from any amino protecting group well known in the field of beta-lactam chemistry and may be one or two such groups, preferably one such group, for example, acyl groups, including alkanoyl and haloalkanoyl groups as defined above in relation to hydroxy protecting groups which may be represented by R ³ , preferably formyl, acetyl, chloroacetyl and propionyl groups, and arylcarbonyl groups in which the aryl part may be as defined above as defined above and exemplified below, preferably benzyl zoylová group, and oxycarbonyl groups, which may be as defined above in relation to protecting groups on the hydroxy group which may be represented by R ^3, preferably benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, allyloxycarbonyl,

2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, tert-butoxycarbonyl, and 2g (trimethylsulphethoxycarbonyl) groups of the formula -C (= NR ¹⁰ ) NR ¹¹ R ¹² and -NR ³ C (= NR ² · ⁴⁾ ) R ^{15, R} and R ^x are independently selected from the group consisting of hydrogen atoms, amino protecting groups as for example, were defined and exemplified above in relation to the alkyl groups which may be represented by a, preferably a methyl or ethyl 11 12 group, or R and R together represent a group of formula - (CH 2) -, wherein n is an integer from 2 to 6, or 10 11 ⁿ

R and R together represent - (CH 2) -,

P wherein p is 2 or 3, and R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, for example as defined and exemplified in relation to alkyl groups which may be represented by A, preferably a methyl, ethyl or propyl group , amino or protected amino, for example as defined and exemplified above, or any two of R @ 3, R @ ^14, _and R @ 5 -5 together represent a group of formula - (CH3) - wherein p is 2 or 3.

zp ^{c J} ,

Í!>

i ·.

When A is an aryl group, it is a carbocyclic aromatic group having from 6 to 14, preferably from 6 to 10, more preferably 6 or 10, and most preferably 6 carbon atoms in the ring, in one or more aromatic rings. The group may also be unsubstituted or substituted and, if substituted, the substituents are selected from the group consisting of the above defined and exemplified C substituents. In the case of the Substituted Groups, there is no particular limitation on the number of substituents on the aryl groups up to and including may be comprised of a number of substitutable positions or possibly steric constraints, but generally from 1 to 5 substituents are preferred, more preferably from 1 to 4 substituents, and 1, 2 or 3 substituents are most preferred. Also, where the group is substituted, it is preferred that it is not further substituted by a group that is also substituted by another aryl group. Specific examples of aromatic groups include phenyl, alpha- or beta-rthaphthyl, indenyl, phenanthrenyl and anthracenyl groups, of which preference is given

, .- x ^R7 if such aromatic hydrocarbon groups having 6 to 10 ring carbon atoms, especially phenyl, alpha-naphthyl and beta-naphthyl groups, most preferably phenyl.

When the aryl group is substituted, the substituents are selected from the group consisting of C substituents, including:

alkyl groups having from 1 to 6 carbon atoms, which may be straight or branched chain groups and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 2- methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,

1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups, of which alkyl groups having from 1 to 4 carbon atoms are preferred, preferably methyl, ethyl, propyl isopropyl, butyl and isobutyl groups most preferably methyl, ethyl, propyl and isopropyl groups and most preferably methyl, alkoxy groups having from 1 to 6 carbon atoms which may be a straight or branched chain group, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy- , isobutoxy-, sec-butoxy-, t-butoxy-, pentyloxy-, isopentyloxy-, neopentyloxy-, 2-methylbutoxy-, 1-ethylpropoxy-, 4-methylpentyloxy-, 3-methylpentyloxy-, 2-methylpentyloxy-, 1- methylpentyloxy-, 3,3-dimethylbutoxy-, 2,2-dimethylbutoxy-, 1,1-dimethylbutoxy-, 1,2-dimethylbutoxy-, 1,3-dimethylbutoxy-, 2,3-dimethylbutoxy-, 2-ethylbutoxy-, hexyloxy- and isohexyloxy, of which ex preferably those alkoxy groups having from 1 to 4 carbon atoms, preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy, most preferably methoxy, ethoxy and propoxy groups, and most preferably methoxy, halogen atoms such as fluorine, chlorine atoms , bromine and iodine, especially fluorine, chlorine and bromine, '* alkoxycarbonyl groups having 2 to 7 carbon atoms, that is the alkoxy part has from 1 to 6 carbon atoms and may be any of the alkoxy groups defined and _T example mentioned, examples of such alkoxycarbonyl groups include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxykarbonylová, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2 -methylpentyloxyka 1-methyl-1-methyl-pentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl

2,3-dimethylbutoxycarbonyl, 2-ethylbutoxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups, of which those alkoxycarbonyl groups having from 1 to 4 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl groups, more preferably methoxycarbonyl and ethoxycarbonyl, groups, groups of the formula -CONR ⁸ , ⁹ ,. _R 8 _, 9. . .

, καε κ and R are the same or different ·% ': 5 and each represents a hydrogen atom, a protective group on an amino group,

For example as defined above and examples given in relation to the groups (s) which may be included in substituents A, alkyl groups having from 1 to 6 carbon atoms, as exemplified above in relation to substituents C, or phenyl, or R and R together represent a group of the formula - (ΟΟ Ιθ-Ο ^ ίΟΙ ^ δ-), wherein q and are independently selected from the group consisting of 0 and integers from 1 to 5 and r are 0 or 1, provided that (q + s) is an integer of at least 2, and cyano, hydroxy and nitro.

When A is an aralkyl group, this group is as defined above and the examples include any alkyl groups having from 1 to 6, preferably from 1 to 4 carbon atoms, the above examples and substituted with at least one aryl group such as those exemplified above. . There is no particular restriction on the number of aryl substituents except those which may be induced by the number of suitable substitutable positions or possibly steric constraints, but generally from 1 to 3 aryl groups are preferred, 2 or 1 being more preferred and one aryl being most preferred group. The aryl group forming part of the aralkyl group may itself be unsubstituted or may be substituted by at least one substituent selected from the group consisting of substituents C, as defined and exemplified below. Again, there is no particular restriction on the number of substituents on the aryl group, except for those which may be induced by the number of substitutable positions or possibly by atheric constraints, but generally from 1 to 5 substituents are more preferred, from 1 to 3 being more preferred. most preferred is one substituent. Specific examples of such groups include benzyl, alpha-naphthylmethyl, beta-naphthyl methyl, 2-methylbenzyl, 3-methylbenzyl, 4-methyl28 benzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 2-methoxybenzyl, 3 -methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, alpha- or beta-naphthylmethyl, benzene (i.e. diphenylmethyl), trityl (i.e. triphenylmethyl), phenethyl, 1-phenethyl, 1- (alpha- or beta-naphthyl) ethyl, 2- (alpha- or beta-naphthyl) ethyl, 1-phenylpropyl, 2-phenylpropyl 3-phenylpropyl, 1- (alpha- or beta-naphthyl) propyl, 2- (alpha, or beta-naphthyl) propyl, 3- (alpha- or beta-naphthyl) propyl, 1-phenylbutyl, 2-phenylbutyl, 3 -phenylbutyl,

4-phenylbutyl, 1- (afa- or beta-naphthyl) butyl, 2- (alpha or beta-naphthyl) butyl, 3- (alpha or beta-naphthyl) butyl, 4- (alpha or beta-naphthyl) butyl, 1-phenylpentyl,

2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1- (alpha- or beta-naphthyl) pentyl, 2- (alpha or beta-naphthyl) pentyl, 3- (alpha- or beta-naphthyl) pentyl, 4- (alpha- or beta-naphthyl) pentyl, 5- (alpha- or beta-naphthyl) pentyl, 1-phenylhexyl, 2-phenylhexyl,

3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1- (alpha- or beta-naphthyl) hexyl, 2- (alpha- or beta-naphthyl) hexyl, 3- (alpha- or beta-naphthyl) hexyl, 4- (alpha- or beta-naphthyl) hexyl, 5- (alpha- or beta-naphthyl) hexyl, and 6- (alpha- or beta-naphthyl) hexyl groups. Of these, benzyl, phenethyl, 3,3'-phenylpropyl and 4-phenylpentyl groups are preferred, unsubstituted aralkyl groups being more preferred and unsubstituted benzyl and phenethyl groups which are

J most preferred.

When A is a heterocyclic group, this group has from 3 to 10, more preferably from 5 to 7 ring atoms, in one or more heterocyclic rings, at least one of said atoms, preferably from 1 to 4 and much more

- '. i ‘li

More preferably from 1 to 3 of said heteroatoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, said group being unsubstituted or substituted by at least one substituent selected from the group consisting of B on carbon atoms, B ^X on nitrogen heteroatoms and oxygen atoms to form a sulfinyl or sulfonyl group on the sulfur heteroatoms, all being as defined and defined below, or may be a fused heterocyclic group in which the heterocyclic group is as defined above and. is condensed. to an aryl group as defined above, preferably to a phenyl group. The heterocyclic group may be aromatic or non-aromatic, preferably non-aromatic. The group may be a monocyclic group or may consist of two or more rings attached to each other by fusion or spiro attachment. In the case of groups having 4 ring heteroatoms, it is preferred that 3 or 4 of them are nitrogen atoms, and 1 or 0 are oxygen or sulfur atoms. In the case of such groups having 3 ring heteroatoms, it is preferred that 1, 2 or 3 are nitrogen atoms and 2, 1 or 0 are oxygen and / or sulfur atoms. ry. In the case of such groups having 1 or 2 heteroatoms, * in the ring, the heteroatoms may be freely selected from nitrogen, oxygen and sulfur aromas. Preferably, however, the group contains at least one nitrogen atom. The group may be substituted or unsubstituted and, if substituted, the substituents are selected from the group consisting of substituents B, B ^X and oxygen atoms as defined above and exemplified below.

The groups may also be saturated, unsaturated or substituted; ¹ 'partially saturated and if fully unsaturated may have an aromatic character. Examples of such non-aromatic groups include azetidinyl, pyrrolidinyl, oxopyrrolidinyl, piperidinyl, oxopiperidyl, morpholinyl, especially morpholine, thiomorpholine, tetrahydropyrimidinyl, thiazolidinyl, oxazolidinyl, hexahydrbpyrimidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl, imidazolidinyl and imidazolidinyl groups. Of these, saturated heterocyclic groups having 5 or 6 ring atoms containing at least one nitrogen atom and optionally oxygen or sulfur atom (s) are preferred. ,

These heterocyclic groups may optionally be fused with one or more other cyclic groups such as, for example, aryl and cycloalkyl groups as defined and exemplified. Examples of such groups include 1,2,3,4-tetrahydroisoquinolyl, pyrazolotriazollyldecahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, decahydroquinolyl, isoindolinyl and indolinyl groups.

Where A is a substituted alkyl group, it has from 1 to 6 carbon atoms and is substituted by at least one substituent selected from the group consisting of the heterocyclic groups and the linked heterocyclic groups defined and exemplified above.

Such heterocyclic groups and heterocyclic groups which are substituents on the alkyl groups represented by A may be unsubstituted or may be substituted by one or more of the following groups and atoms.

There is no particular restriction on the number of substituents that may be present, except for those induced by the number of substitutable atoms, and possibly by steric restrictions. In general, a preferred number of from 1 to 5 substituents is more preferred is from 1 to 3 substituents. >

In the case of carbon atoms or sulfur atoms, these atoms may be substituted by 1 (carbon atoms) or 2 (sulfur atoms) oxygen atoms to form a carbonyl group or a sulfinyl or sulfonyl group.

In the case of carbon atoms, these atoms may be substituted by one or more substituents B:

alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,

1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and isopentyl groups alkoxy groups having from 1 to 6 carbon atoms, such as methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, pentyloxy-, isopentyloxy-, neopentyloxy-, 2- methylbutoxy-, 1-ethylpropoxy-, 4-methylpentyloxy-, 3-methylpentyloxy-, 2-methylpentyloxy-, 1-methylpentyloxy-, 3,3-dimethylbutoxy-, 2,2-dimethylbutoxy-, 1,1-dimethylbutoxy-,

1,2-dimethylbutoxy-, 1,3-dimethylbutoxy-, 2,3-dimethylbutoxy-, 2-ethylbutoxy-, hexyloxy- and isohexyloxy-, preferably methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, sec. butoxy and tert-butoxy, hydroxy, cyano, nitrosadines, halogen atoms such as fluorine, chlorine, bromine and iodine atoms, alkoxycarbonyl groups having from 2 to 7 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonylcarbonyl, isopropoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl , sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 2-methylcarbonyl, , 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethyl _with butoxycarbonyl, 2,3-dimethylb utoxycarbonyl,

2-ethylbutoxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups, preferably the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert sek.butoxykarbonylové, butoxycarbonyl, carboxy ^f s' and a cycloalkyl group having 3 to 7 ring carbon atoms, preferably 5 or 6 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and · the alkoxy groups in which the alkoxy and ^{alkyl! Í} part both have from 1 to 6 carbon atoms, and each may have f meanings as above defined, and examples given in relation to those groups included in substituents B, including, for example, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, 2-methoxymethyl, 3-methoxypropyl,

Even ^with 2-methoxypropyl or 4-ethoxybutyl. ...

. .

íw ‘í r« <.

'-'and

Alkoxycarbonylalkyl groups in which the alkoxy and alkyl moieties both have from 1 to 6 carbon atoms and each may have the meaning as defined above and the examples given in relation to the groups included in substituents B, for example methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl butoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl,. 2-methoxycarbonylpropyl and 4-ethoxy. carbonylbutyl groups, ........

cyanoalkyl groups in which the alkyl moiety has from 1 to 6 carbon atoms, such as cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl and 4-cyanobutyl groups, haloalkyl groups having from 1 to 6 carbon atoms in which the alkyl moiety may be any of the above alkyl groups and having at least one halogenated substituent, there is no limitation on the number of halogenated substituents, and the group may be any group from a monohaloalkyl group to a perhalogen group, preferably from 1 to 3 halogen atoms, examples of such groups include trifluoromethyl, trifluoromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl,

2-fluoropropyl, 4-chlorobutyl and 3-fluorobutyl groups, alkanoyloxy groups having from 1 to 6 carbon atoms, such as acetoxy-, propionyloxy-, butyryloxy-, isobutyryloxy-, valeryloxy-, isovaleryloxy-, pivaloyloxy- and hexanoyl-34 oxy groups, preferably acetoxy- , propionyloxy-, butyryloxy or isobutyryloxy, azido, alkylthio groups having from 1 to 6 carbon atoms, such as methylthio-, ethylthio-, propylthio-, isopropylthio-, butylthio-, isobutylthio-, sec-butythio-, tert-butylthio-, tert-butylthio- isopentylthio-, neopentylthio-, 2-methylbutylthio-, 1-methylpropylthio-, 4'-methylpentylthio-, 3-methylpentylthio-, 2-methylpentylthio-, 1-methylpentylthio-, 3,3-diraethylbutylthio-, 2,2-dimethylbutylthio- 1,1-dimethylbutylthio-, 1,2-dimethylbutylthio-, 1,3-dimethylbutylthio-, 2,3-dimethylbutylthio-, 2-ethylbutylthio-, hexylthio- and iso-hexylthio, preferably methylthio- ethylthio-, propylthio-, isopropylthio-, butylthio and isobutylthio groups, alkylsulfinyl groups m ající 1 to 6 carbon atoms such as methylsulfinyl, ethylsulfinyl, propylsulfiny _in) nominal, isopropylsulfinyl, butylsulfinyl, isobutylsul / alkanoylamino, butylsulfinyl, tert, pen7 / tylsulfinylové, isopentylsulfinylové, neopentylsulfinylové,

2-Methylbutylsulfinyl, 1-ethylpropylsulfinyl, 4-methylpentylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl, 3,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl 2-dimethylbutylsulphinyl, 1,3-dimethylbutylsulphinyl, 2,3-dimethylbutylsulphinyl, 2-ethylbutylsulphinyl, hexylsulphinyl and isohexylsulphinyl groups, preferably methylsulphinyl, ethylsulphinyl, propylsulphinyl / isopropylsulphinyl / isopropylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinylsulphinyl

- alkylsulfonyl groups having from 1 to 6 carbon atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, neopentylsulfonyl, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl, 3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 2-ethylbutylsulfonyl, hexylsulfonyl and isohexylsulfonyl groups, preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl and isobutylsulfonyl groups,

Groups of formula -NR R and groups of formula -CONR R, wherein

9,

R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having 1 to 6 carbon atoms and phenyl groups, or R and R together are - (CH 2) -O- (CH 2) ) -, wherein q and s are independently 2 qr 2s selected from the group consisting of 0 and integers from 1 to 5 and r are 0 or 1, provided that (q + s) is an integer at least 2 as defined above and the examples given , and groups of formulas BI, B-II, B-III, B-IV, BV, B-VI,

B-VII, B-VIII and B-IX as shown above.

In Formulas B-I, B1-I to B-IX,. *

R represents a hydrogen atom, an amino protecting group (as exemplified above in relation to A),

--- 7

--1 i v- * i

4 $

I, 4 i

g a group of formula -COR, wherein

R represents an alkyl group having from 1 to 6 carbon atoms, such as the groups exemplified above in relation to R 6, preferably a methyl group, or a substituted alkyl group having from 1 to 6 carbon atoms and substituted with one substituent selected from the group consisting of R A, -C (= NR ¹⁶⁾ R ^17, wherein

R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, as exemplified above in relation to methyl, amino, protected amino groups, as exemplified above in relation to A, and amino protecting groups such as those exemplified above with respect to A, an unsubstituted alkyl group having from 1 to 6 carbon atoms, such as those exemplified above with respect to methyl, or a substituted alkyl group having from 1 to 6 carbon atoms. 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of substituents D, as defined and exemplified below,

22nd

R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, such as those exemplified above in relation to R ¹ , preferably methyl, hydroxy and protected hydroxy groups, as defined above and examples as referred to in R ⁸ ,

2 9

R and R are independently selected from the group consisting of ¹ hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms such as those exemplified above in relation to R, preferably methyl, amino protecting groups such as those exemplified above and A, and amino groups, protected amino groups, such as those exemplified above in relation to A, and groups of formula -C (= NR4) R, wherein and are as defined above.

R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, such as those exemplified above, preferably methyl, or a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one substituent selected from a group consisting of hydroxy groups, for example 1-hydroxyethyl, and protected hydroxy groups such as those defined above and examples given in relation to R 1.

R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms per se, as exemplified above in relation to R1, preferably a methyl group, or an amino-protecting group as exemplified above in relation to A.

R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, as exemplified above in relation to r 1, preferably a methyl group, or a group of the formula

2828 28 29

-NR R, wherein R and R are as defined above.

E represents an imidazolyl group or a triazolyl group. ^s , · ► '

W represents an aromatic heterocyclic group having from 5 to 8, preferably 5 or 6 ring atoms, of which from 1 to 4 are nitrogen atoms, said heterocyclic group being unsubstituted or substituted by at least one alkyl group having from 1 to 6 carbon atoms, such as those exemplified above in relation to R0 preferably methyl, specific examples of such aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, triazolyl and tetrazolyl groups. , «

Where, as preferred, there is a nitrogen atom in the heterocyclic group, it may also be substituted and the substituents are selected from the group consisting of B 1 substituents, including:

alkyl groups having from 1 to 6 carbon atoms, as exemplified above in relation to R ^, preferably methyl, a group of the formula -C (= R ^ ³ ) R ^ ⁷ , wherein R ^ ³ and R ^ ⁷ have the above said meaning and examples said meaning, amino-protecting groups, as exemplified above: _p

2) denoted in relation to the A, a, '-f group of the formula -CONr ¹ R ^1' , wherein r ¹⁸ and R ^{1 '} are independently selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, such as the above examples in relation to R 1, the advantages. 'Λ?' methyl, ethyl, propyl or isopropyl. and carboxyl acyl groups, preferably oxycarbonyl groups, as defined above and exemplified in relation to oxycarbonyl groups which

R can be represented.

 and

/ 4%

>

. '&

The substituents D are selected from the group consisting of hydroxy-protected hydroxy groups as defined above and examples given in relation to R1, carboxy-protected carboxy groups as defined above and examples given in relation to R1, cyano, alkoxy groups having from 1 to 6 carbon atoms, such as those defined above and examples given in relation to R, preferably methoxy, alkylsulfonyl groups having from 1 to 6 carbon atoms, such as those given above in relation to substituents B, and a group of the formula

9 9 4 9 9 9 4 9 5 9496 23

-NKCOR, -NR R, -CONR R or -OCONR R, where R,

R ¹⁴ and R 25 are independently selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 6 carbon atoms, as exemplified above in relation to R 4, preferably methyl, ethyl, propyl or isopropyl.

When R is an alkyl group, it may be a group as defined above and examples given. The group may be unsubstituted or it may be substituted by one or more substituents selected from the group consisting of substituents E, including: hydroxy, protected hydroxy groups as defined above and examples given in relation to R, amino and protected amino groups such as those set forth in relationship to A.

When R is alkenyl, it has from 2 to 6, preferably 3 or 4 carbon atoms and is unsubstituted or substituted by at least one substituent selected from the group of the above defined and examples of said E substituents. Examples include vinyl, allyl, methallyl , 1-propenyl, isopropenyl, 1-bufenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl and 4-pentenyl groups, of which vinyl, allyl, 1-propenyl and 1- butenyl groups and most preferred are vinyl, allyl and 1-butenyl groups.

When R is an aryl or aralkyl group, it may be any aryl or aralkyl group as defined and exemplified above with respect to A, and, as with A, may be substituted or unsubstituted.

When R represents a cycloalkyl group, this group has from 3 to 7 carbon atoms and is unsubstituted or substituted by at least one of the substituents selected from the group consisting of substituents C, as defined above and examples. Preferred cycloalkyl groups have from 4 to 6 carbon atoms and examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups, of which cyclobutyl, cyclopentyl and cyclohexyl groups are preferred.

When R R represents an aromatic heterocyclic group, this group has from 5 to 7, preferably 5 or 6 ring atoms, in the aromatic heterocyclic ring, which may optionally be fused with an aryl group as defined above and examples given, preferably by a phenyl group.

. The group has at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms, and preferably has from 1 to 4, and most preferably 1 or 2, such heteroatoms. In the case of such groups having 4 ring heteroatoms, it is preferred that 1, 2 or 3 of them are nitrogen atoms and 1 or 0 oxygen or sulfur atoms. In the case of such groups having 3 ring heteroatoms, it is preferred that 1, 2 or 3 are nitrogen atoms and 2, 1 or 0 are oxygen and / or sulfur atoms. V pří. dropping such groups having 1 or 2 ring heteroatoms,. the heteroatoms may be freely selected from nitrogen, oxygen, and sulfur atoms. Preferably, however, the group contains at least one nitrogen atom. Examples of such aromatic heterocyclic groups include 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-imidazolyl, 3-thiazolyl, 2-thienyl and 2-furyl groups.

J groups. These groups may be unsubstituted or may have one or more substituents selected from the group consisting of the above defined and exemplified C substituents.

'4.

In the case where R represents an alkyl group having p. 1 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of aromatic _w sneezes heterocyclic groups and fused heterocyclic groups, the heterocyclic groups can have the meanings as defined and exemplified above and the alkyl groups may be any of alkyl groups having from 1 to 6, preferably from 4 to, and more preferably 1, 2 or 3 carbon atoms as defined above and examples given in relation to R, etc., most preferably methyl and ethyl groups.

In compounds of formula IV, R ¹ may be the same as in compounds of formula I and II. In these compounds, particularly preferred groups for _R are:

alkyl groups, in particular methyl, ethyl and i. tert-butyl groups,

- aralkyl groups, in particular benzyl, benzhydryl groups,

4-nitrobenzyl and 2-nitrobenzyl groups,

I · ..

alkenyl groups, especially allyl, 2-chlorallyl and 2-methylallyl groups, haloalkyl groups, especially 2,2,2-trichloroethyl and 2,2,2-tribromethyl groups, and

_a '2-trimethy.lsilylethylova group.

ig. Also, R ⁴ may be a hydrogen atom or a protective group, a pin on the hydroxy group, which may be any of the groups

Particularly preferred groups in the case of R 1 _{SO 2 are} :

tri-substituted silyl groups such as those exemplified above, in particular tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl and triethylsilyl, aralkyloxycarbonyl groups as defined above, and examples thereof, preferably benzyloxycarbonyl and 4-nitrobenzyloxycarbonyloxycarbonyloxycarbonyl and substituted acetyl groups, especially those in which the substituents are selected from the group consisting of substituents C, as defined and exemplified above, and in particular acetyl, chloroacetyl and methoxyacetyl groups.

43

R, R, R and R may be an alkyl group having from 1 to 6 carbon atoms, which may have the meaning as defined above and the examples given in relation to R and R. Particularly preferred such groups are methyl, ethyl, propyl, isobutyl, pentyl and hexyl groups, most preferably methyl, ethyl and propyl groups.

43

R @ 1 and R @ 2 may be alkoxy having from 1 to 6 carbon atoms, which may have the meaning as defined above, n, 7 and examples given in relation to R @ 1. Particularly preferred groups are methoxy, ethoxy, propoxy, isobutoxy, pentyloxy and hexyloxy groups, of which methoxy, ethoxy and propoxy are most preferred. ►

43

R 2 and R 2 may be halogen, for example fluorine, chlorine. bromine or iodine of which they are

Preferred are fluorine, chlorine and bromine atoms and are most preferably fluorine and chlorine atoms. .

R ⁴ , R ^3, and R ⁴ may be an aryl group, which may have the meaning as defined above and the examples given with respect to r ⁵ A particularly preferred such group is a phenyl group. Where R is aryloxy, it may be an aryloxy equivalent of any of the aryl groups defined above and exemplified in relation to R. A particularly preferred such group is phenoxy.

Preferred compounds of formula I are those in which

R ^ means:

a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aralkyl group which is an alkyl group having from 1 to 4 carbon atoms, substituted by at least one aryl group as defined above, an alkenyl group having from 2 to 6 carbon atoms which is unsubstituted or substituted by one or more halogen atoms, a haloalkyl group having from 1 to 6 carbon atoms, a tri-substituted silylethyl group in which all three or two or one of the substituents are alkyl groups having from 1 to 5 carbon atoms, and none one or two of the substituents are aryl groups as defined above,

An acyloxyalkyl group wherein the acyl moiety is an alkanoyl group having from 1 to 6 carbon atoms and the alkyl moiety has from 1 to 6 carbon atoms, an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl moieties each have from 1 to 6 carbon atoms, cycloalkoxycarbonylcxyalkyl groups wherein the cycloalkyl moiety has from 3 to 7 carbon ring atoms and may be unsubstituted or substituted with at least one substituent selected from the group consisting of the above defined C substituents and the alkyl moiety has from 1 to 6 carbon atoms, (5-alkyl- or 5- an aryl-2-oxo-1,3-dioxolen-4-yl) methyl group in which the alkyl moiety has from 1 to 4 carbon atoms and the aryl moiety is as defined above;

3-phthalidyl group,

3 (2) R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, and groups of the formula

wherein R represents a hydrogen atom or a methyl group, and R 0 represents:

-AND

V) • 3 '4

- 45 hydrogen, a substituted silyl group in which the silyl group has three substituents selected from alkyl groups having from 1 to 6 carbon atoms and phenyl groups, an aralkyl group in which the alkyl group having from 1 to 4 carbon atoms is substituted with at least one of the above an aralkyloxycarbonyl group in which the aralkyl moiety is as defined above, an alkenyloxycarbonyl group in which the alkenyl ^f moiety has from 2 to 6 carbon atoms and is unsubstituted or substituted by at least one halogen atom, an alkoxycarbonyl group having from 2 to 6 A substituted silylalkoxycarbonyl group in which the alkoxycarbonyl moiety and the substituted silyl moiety are as defined above; an oxygen-containing heterocyclic group; an alkoxyalkyl group in which the alkoxy and alkyl moieties each have from 1 to 7 carbon atoms; up to 6 carbon atoms, a substituted silylalkoxyalkyl group in which the alkoxyalkyl moiety and the substituted silyl moiety are as defined above, or.

an alkanoyl or haloalkanoyl group having no more than 6 carbon atoms, or

3 6

R and R together represent a group of the formula = C (CH3) CH, OR, in which R is as defined above, (3) X is a sulfur atom or a group of formula> CHR wherein 7

R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, or an alkoxy group having from 1 to 4 carbon atoms, and (4) A represents an alkyl group having from 1 to 4 carbon atoms and is unsubstituted or substituted by 1; 2 substituents selected from the group consisting of the following substituents A ^and , an aryl group as defined below, an aralkyl group in which an alkyl group having from 1 to 3 carbon atoms is substituted with at least one aryl group as defined below, a heterocyclic group having from 4 up to 7 ring atoms, at least one of said atoms being a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, said group being unsubstituted or substituted by at least one substituent selected from the group consisting of B ^and C, B ^and C 1-4 substituents nitrogen heteroatoms and oxygen atoms to form a sulfinyl or sulfonyl group on h the alkyl ether having from 1 to 3 carbon atoms and which is substituted by at least one substituent selected from the group consisting of the above-defined heterocyclic groups, said aryl groups being aromatic carbocyclic groups having from 6 to 19 carbon atoms in ring and are nesubstituovahé or are substituted by at least one substituent selected from substituents C, defined below ^and said substituents ^a are selected from the group consisting of hydroxy, protected hydroxy, amino, protected amino groups, groups of formula

-C (= NR ¹⁰ ) NR ^11; R ¹² , wherein R ¹⁰ , R ⁶ and R ³ · ² are independently selected from the group consisting of hydrogen atoms, amino protecting groups and alkyl groups having from 1 to 4 atoms

12,. or R and R together represent a group of formula - (CH 2) -, wherein n is an integer from 2 to 6, or R 10 and 11 n -.

R together represent a group of the formula - (CH_) - wherein p is 2 or 3, and a group of the formula -NR ' ¹ ' ³ C (= NR ^{4 '} ) R ³ ' ³ , wherein

R ³ · ⁸ and R ³ · 4 are independently selected from the group consisting of hydrogen atoms, amino protecting groups and alkyl groups having from 1 to 6 carbon atoms, and ar 5 is hydrogen, alkyl having from 1 to 4 atoms or any two of R ³³ , R ^3, and R ³³ together represent a group of the formula wherein p is 2 or 3, said substituents B ^and are selected from the group consisting of:

-?

• 4 alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms;

hydroxy groups,. w halogen atoms, cyano groups, nitro groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, carboxy groups, oxygen atoms to form a carbonyl group with a ring carbon atom, alkoxyalkyl groups in which the alkoxy and alkyl moieties have from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms,

Even alkanoyloxy groups having from 1 to 6 carbon atoms,

The groups of formula -NR R and groups of the formula -CONR R, wherein r 8 _and r 9 are _SO independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having from 1 to 4 carbon atoms, 8 9 and phenyl groups or R and R together represent a group of the formula - (CH,) O - (CH-) -, wherein q and s are independently selected from the group consisting of 0 and integers from 1 to 5 and r are 0 or 1, provided that: that (q + s) is an integer at least 2, and groups of formulas BI, B-II, B-III, B-IV, BV, B-VI, B-VII, B-VIII, and B-IX, as defined above, said substituents B ^and Q are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, protecting groups on the amino group, groups of the formula -C (= NR) R, gi 7 wherein R is and R are as defined above, protecting groups on the amino group and groups of the formula -CONR R, wherein

19 Dec

R and R are independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms and benzoyl groups, said C substituents being selected from the group consisting of alkyl groups having from 1 to 4 atoms carbon, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms, groups of the formula -CONR 6 R 6, wherein R 6 and R 6 are as defined above, cyano, hydroxy and nitro.

More preferred compounds of formula I and II of the invention are those wherein:

(5) R ^ means:

a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aralkyl group having an alkyl group having 1 or 2 carbon atoms substituted by at least one phenyl group, a haloalkyl group having from 1 to 4 carbon atoms, a tri-substituted silylethyl group in which all three or two of the substituents are alkyl groups having from 1 to 4 carbon atoms, and none or one of the substituents is phenyl, an acyloxyalkyl group in which the acyl moiety is an alkanoyl group having from 2 to 5 carbon atoms and the alkyl moiety has 1 or 2 carbon atoms, an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl moieties each have from 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxolenr-4-yl) methyl, or

3-phthalidyl,

3 (6) R and R are independently selected from the group consisting of '5' from hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, and groups of the formula:

CH

AND

R '

Μ

-4 · 3

STEED

'WITH

-51 wherein r5 represents a hydrogen atom or a methyl group and R represents:

a hydrogen atom, a substituted silyl group in which the silyl group has 3 substituents selected from alkyl groups having from 1 to 4 carbon atoms and phenyl groups, an aralkyl group in which the alkyl group having from 1 to 4 carbon atoms is substituted with at least one aryl group, as defined above, an alkoxycarbonyl group having from 2 to 7 carbon atoms, a tetrahydropyranyl group, an alkoxyalkyl group in which the alkoxy moiety and an alkyl moiety each have from 1 to 4 carbon atoms, an alkanoyl or haloalkanoyl group having from 2 to 7 carbon atoms Or 5 carbon atoms;

R ^J and R together represent a group of formula ^ (CH ^ OR ^ JCI in which R® is as defined above, (7) X represents a sulfur atom or a group of the formula> CHR ^, where

'.XX

R represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms or an alkoxy group having 1 or 2 carbon atoms, and (8) A represents a hydrogen atom;

an alkyl group having 1 or 2 carbon atoms and which is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of substituents A as defined below, a phenyl group which is unsubstituted or is sub-.

substituted with 1 or 2 substituents selected from the group consisting of C, "aralkyl" as defined below, wherein the alkyl group having from 1 to 3 carbon atoms is substituted with at least one phenyl group which is unsubstituted or substituted with 1 or 2 substituents selected from the group below defined substituents C, a heterocyclic group having 5 or 6 ring aromas, 1 to 3 of said atoms being heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, said group being unsubstituted or substituted by at least one substituent selected from the group consisting of B 0 substituents on carbon atoms, substituents on nitrogen heteroatoms, and oxygen atoms to form a sulfinyl or sulfonyl group on sulfur heteroatoms, all as defined below, said A 0 substituents being selected from the group consisting of hydroxy, protected hydroxy groups, and amines; and substituted amino groups, said substituents being selected from the group consisting of alkyl groups having 1 or 2 carbon atoms;

j ©,

·. » alkoxy groups having 1 or 2 carbon atoms, hydroxy groups, halogen atoms, cyano groups, nitro groups, etc.

alkoxycarbonyl groups having from 2 to 5 carbon atoms,

Μ

'ι'-ί ··, Λ

carboxy groups, haloalkyl groups having from 1 to 6 carbon atoms, alkanoyloxy groups having from 1 to 6 carbon atoms,

Groups of formula -NR R and groups of formula -COUR R, wherein R _x and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having 1 or 2 carbon atoms, and 8 9 phenyl groups or R and R together represent a group of formula - (CH ₂₎ Go _R - (CH _{2) g} - in which QAS are independently selected from the group consisting of 0 and integers 1 to 5 and r is 0 or 1, provided that (q + s) is an integer of at least 2, and the groups of formulas BI, B-II, B-III, B-IV, BV, B-VI, B-VII, B-VIII and B-IX as above are defined from the group consisting of said substituents B1

^:, Ν »alkyl groups having 1 or 2 carbon atoms, amino protecting groups, groups of formula -C (= NR ³³⁾ R ^37,

17 wherein R and R are as defined above, protecting groups at the amino group or groups of formula -CONR ³ R ^^, wherein

R ³³ and R ³ are independently selected from the group consisting of alkyl groups having 1 or 2 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, and benzoyl groups, substituents C are selected from the group consisting of alkyl groups having 1 or 2 atoms carbon, alkoxy groups having 1 or 2 carbon atoms, halogen atoms, groups of the formula -CNR R, where R and R are as defined above, cyano, hydroxy and nitro.

Preferred compounds of formula IV of the invention are those wherein:

(9) R ³ means:

a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aralkyl group, an alkyl group having from 1 to 4 carbon atoms, which is substituted by at least one aryl group as defined above, an alkenyl group having from 2 to 6 carbon atoms and which is unsubstituted or substituted by one or more halogen atoms, a haloalkyl group having from 1 to 6 carbon atoms,

a tri-substituted silylethyl group in which all three or two or one of the substituents are alkyl groups having from 1 to 5 carbon atoms, and none, one or two of the substituents are aryl groups as defined above, an acyloxyalkyl group in which the acyl moiety is an alkanoyl group having from 1 to 8 carbon atoms and the alkyl moiety having from 1 to 6 carbon atoms, an alkoxycarbonyloxyalkyl group wherein the alkoxy and alkyl moieties each have from 1 to 6 carbon atoms, a cycloalkoxycarbonyloxyalkyl group wherein the cycloalkyl moiety has from 3 up to 7 ring carbon atoms and may be unsubstituted or substituted by at least one substituent selected from the group consisting of C substituents as defined above, and the alkyl moiety has from 1 to 6 carbon atoms, (5-alkyl- or 5-aryl-2-oxo-1, 3-dioxolen-4-yl) methyl group in which the alkyl moiety has from 1 to 4 carbon atoms and the aryl moiety has an alkyl hu defined meaning, or

3-phthalidyl, (10) R ⁴ ^ means:

a hydrogen atom, a substituted silyl group; which silyl group has 3 substituents selected from alkyl groups having 1 to 6 carbon atoms and phenyl groups, an aralkyl group in which the alkyloxy group having 1 to 4 carbon atoms is substituted by at least one aryl group as defined above, an aralkyloxycarbonyl group in which the aralkyl moiety is as defined above, an alkenyloxycarbonyl group in which the alkenyl moiety has from 2 to 6 carbon atoms and is unsubstituted or substituted by at least one halogen atom, an alkoxycarbonyl group having from 2 to 7 carbon atoms,

... a substituted silylalkoxycarbonyl group in which the alkoxycarbonyl moiety and the substituted silyl moiety are as defined above,

an oxygen-containing heterocyclic group, an alkoxy group in which the alkoxy and alkyl moieties each have from 1 to 6 carbon atoms, a substituted silylalkoxyalkyl group in which the alkoxyalkyl moiety and the substituted silyl moiety are as defined above, or alkanoyl or (11) R represents an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, an "atom of halogen", an aryl group as defined below, or an aryloxy group, in (12) R ⁴² represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a hydroxy group, a halogen atom, a cyano group, a nitro group or a group of the formula -NR R wherein R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups, h groups having from 1

9 to 4 carbon atoms and phenyl groups, or R and R together represent a group of the formula - (CH ₂ ) q -O _r - (CH ₂ ) _g -, wherein q and are independently selected from the group consisting of 0 and integers from 1 to 5 ar ja C or 1 ", provided that (q + s) is an integer of at least 2, and

46.

(13) R and R are independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms and the below defined aryl groups, or R and R together represent a group of the formula - (CH ₂ ) (CH ₂ ) _S -, q and are independently selected from the group consisting of 0 and integers from 1 to 5; and r is 0 or 1.

More preferred compounds of formula IV are those wherein:

(14) r! means:

a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aralkyl group, an alkyl group having 1 or 2 carbon atoms which is substituted by at least one phenyl group, a haloalkyl group having 1 to 4 carbon atoms, a tri-substituted silylethyl group wherein all three or two of the substituents are alkyl groups having from 1 to 4 carbon atoms, and none or one of the substituents is phenyl groups, an acyloxyalkyl group wherein the acyl moiety is an alkanoyl group having from 2 to 5 carbon atoms and an alkyl moiety has 1 or 2 carbon atoms, an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl moieties each have from 1 to 4 carbon atoms, (5-methyl-2-: oxo-1,3-dioxolen-4-yl) methyl, or

3-phthalidyl, said aryl groups are aromatic carbocyclic groups having from 6 to 10 ring carbon atoms and are unsubstituted or substituted by at least one substituent selected from the group consisting of the above-defined substituents C ^a , (15) means:

a hydrogen atom, a substituted silyl group in which the silyl group has 3 substituents selected from alkyl groups having from 1 to 4 carbon atoms and phenyl groups, an aralkyl group in which the alkyl group having 1 or 2 carbon atoms is substituted by at least one of the above aryl groups , an aralkyloxycarbonyl group in which the aralkyl moiety is as defined above, an alkoxycarbonyl group having from 2 to 5 carbon atoms, a tetrahydropyranyl group, an alkoxyalkyl group in which the alkoxy and alkyl moieties each have from 1 to 4 carbon atoms, alkanoyl or (16) R is an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a halogen atom, a phenyl group or a phenoxy group,

3 (17) κ represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a hydroxy group, a halogen atom, a cyano group, a nitro group or a group -NRR wherein R and R are independently selected from groups consisting of hydrogen atoms, amino protecting groups, alkyl groups having 1 or 2 to 9 carbon atoms and phenyl groups, or R and R together represent a group of the formula - (CH_) -O- (CH_) -, wherein q and s are independently £ · 2Γ 2 S visibly selected from the group consisting of 0 and integers from 1 to 5 and r are 0 or 1, provided that (q + s) is an integer of at least 2, and

R ⁴⁵ and R ⁴⁶ (18) are independently selected from the group consisting of alkyl groups having 1 or 2 carbon atoms and phenyl-target, or R ^ ⁴ _and 46 ^ _S ^ _O P _{U known} per group of formula

- (CH 2) -O- (CH-) -, wherein q and s are independently selected from q 2 of a group consisting of 0 and integers from 1 to 5 and r is 0 or 1.

Specific examples of compounds of formulas I and II are shown in Tables 1 and 2 below, and specific examples of compounds of formula IV of the invention are shown in Formulas 1-3 and 1-4, in which the substituents are indicated in one of the following tables 3 and 4, Table 3 refers to Formula 1-3 and Table 4 refers to Formula 1-4. preferred compounds are those having the configuration shown in Formulas I-3a and I-4a. Some of the groups represented by R 1 are shown in the following formulas 1-1 to 1-30.

* j: 1

- • 3}

Her:

Ν ^ /

Ν (Μ)

(1-6)

(1-7)

~ 5 • 1 · i (M

.j #

1a>' ⁷ <ϊ

Ř

(1-13)

 ·?

Μ

PNZ

(1-21)

(1-24) ♦ £ «r

2 $

- 65 N

AND

PNZ

(1-25)

(1-28)

‘8 t

also

(I-3a)

The tables contain the following abbreviations:

* '

AC

All

Azp

Bu iBu

Bz

Et

Imid

Ithiz

Me

Ph

Piz

PNB

PNZ

Pr iPr

Pyr

Pyrd

Pyr z

TBS

Tht

TMS

G acetyl allyl perhydroazepinyl butyl isobutyl benzyl ethyl imidazolyl isothiazolyl methyl phenyl piperazinyl

4-nitrobenzyl

4-nitrobenzyloxycarbonyl propyl isopropyl pyridyl pyrrolidinyl pyrazolidinyl t-butyldimethylsilyl 1-oxotetrahydrothien-3-yl trimethylsilyl hydrogen, TMS, TBS or PNZ

- 68 Table 1

merge R ² R ³ R ⁴ X in C. R ¹ . 1-1 PNB H 1- (G-O) Et 1-PNZ-5-Me ₂ NCO-3 -Pyr Ϊ> CH _(CH3) 1-2 PNB H 1- (G-O) Et -CH ₂ CH ₂ NH.PN ₂ > CH _(CH3) 1-3 PNB H 1- (G-O) Et 4-N0_Bz > CH _(CH3) 1-4 PNB H 1- (G-O) Et Ph > CH _(CH3) 1-5 PNB H 1- (G-O) Et 1- [1- (PNZ.N =) CH] -3-Pyrd > CH _(CH3) 1-6 PNB H 1- (G-O) Et 2- [1-Azp.CO] Ph > CH _(CH3) 1-7 PNB .H 1- (G-O) Et 1-PNZ-5- 4 ¹ f -PNZ.OEt) PizCO] Pyrd > CH 1-8 PNB H 1- (G-Oj Et -CH ₂ -C (NMe ₂ ) = N.PNZ > CH _(CH3) 1-9 PNB H 1- (G-O) Et 1,2-di (PNZ) -4-Pyrz > CH _(CH3) •, 1-10 PNB H 1- (G-O) Et Formula (1-1) > CH _(CH3) - 1-11 PNB H 1- (G-O) Et Formula (1-2) > CH _(CH3) -Ϊ 1-12 PNB H 1- (G-OjEt Formula (1-3) > CH _(CH3) 1-13 PNB H 1- (G-O) Et 1-PNZ-5 -PhSCO- 3 -Pyrd > CH _(CH3) 4 and 1-14 PNB H 1- (G-O) Et 5-oxo-2-pyrd > CH (CH ₃ ) 4ΐ 1 -15 PNB H 1- (G-O) Et 5-oxo-3-pyrd > CH _(CH3) .•E 1-16 PNB H 1- (G-O) Et 2-Oxo-3-Pip > CH _(CH3) • 1-17 PNB H 1- (G-O) Et Formula (1-4) > CH _(CH3) 5 1-18 PNB H 1- (G-O) Et Formula (1-5) > CH _(CH3) 1-19 PNB H 1- (G-O) Et Formula (1-6) > CH (CH ₃ ) -í.i 1-20 PNB H 1- (G-O) Et Formula (1-7) > CH _(CH3) : H 1-21 PNB H 1- (G-O) Et Formula (1-8) > CH _(CH3) 1-22 PNB H 1- (G-O) Et 1-PNZ-5- [4- (2-HOEt)] 1 J -1-PizCO] -3-Pyrd > CH _{CH3) and 1-23 PNB H 1- (G-O) Et Formula (1-9) > CH _(CH3) '1 1-24 PNB H 1- (G-O) Et Formula (1-10) > CH _(CH3) ' 1-25 PNB H 1- (G-O) Et Formula (II-II) > CH _(CH3) and#' 1-26 PNB H 1- (G-O) Et Formula (1-12) > CH _(CH3)

'fc.

Table 1 - cont.

merge

- c. '1 '2 '3 4 R R R R X 1-27 PNB H. 1- (G-0) Et Formula (1-13) > CH (CK ₂ ) 1-28 PNB . H 1- (G-O) Et Formula (1-14) > CH _(CH3) 1-29 PNB H 1- (G-O) Et Formula (1-15) > CH (CK ₂ ) 1-30 PNB . H 1- (G-O) Et- Formula (1-16) ..... > CH _(CH3) 1-31 PNB H 1- (G-O) Et formula (1-7) > CH (CK ₂ ) 1-32 PNB H 1- (G-O) Et Formula (1-18) > CH _(CH3) 1-33 PNB H 1- (G-0) Et Formula (1-19) > CH _(CH3) 1-34 PNB H 1- (G-O) Et Formula (1-20) > CH _(CH3) 1-35 PNB H 1- (G-O) Et Formula (1-21) > CH _(CH3) 1-36 PNB H 1- (G-O) Et Formula (1-22) > CH _(CH3) 1-37 PNB H 1- (G-O) Et Formula (1-23) > CH 1-38 PNB H 1- (G-O) Et Formula (1-24) > CH _(CH3) 1-39 PNB H 1- (G-O) Et Formula (1-25) > CH (CK ₂ ) 1-40 PNB H 1- (G-O) Et Formula (1-26) > CH _(CH3) 1-41 PNB H 1- (G-O) Et Formula (1-27) > CH (CK ₂ ) 1-42 PNB . H ' 1- (G-O) Et Formula (1-28) > CH _(CH3) 1-43 PNB H 1- (G-O) Et 1- [1- (PNZ.N =) Et] -3-Pyrd > CH ₂ 1-44 PNB H 1- (G-O) Et 2- (PN 2 -N = CH-NH) Et > CH ₂ 1-45 PNB H 1- (G-O) Et -ch ₂ ch ₂ nh.pnz > CH ₂ . 1-46 PNB H 1- (G-O) Et 1-PNZ-5-Me ₂ NCO-3-Pyrd > CH ₂ 1-47 All H 1- (G-O) Et 1-PNZ- 5-Me ₂ NCO- 3 -Pyrd > CH _(CH3) 1-48 All H 1- (G-O) Et Formula (1-11) > CH _(CH3) 1-49 All H 1- (G-O) Et 2-Oxo-3-Pip > CH _(CH3) 1-50 All H 1- (G-O) Et 5-oxo-3-Pyr > CH _(CH3) 1-51 PNB Formula (1-, 29) 1- [1- (PNZ.N =) Et] -3-Pyrd > ch ₂ 1-52 PNB H Et 1- [1- (PNZ.N =) Et] -3-Pyrd > ch ₂ 1-53 PNB H 1-HO-1-MeEt 1- [1- (PNZ.N =) Et] -3-Pyrd > ch ₂

- 70 Table 1 - continue.

merge R ² R ³ R ⁴ . - X C. R ¹ 1-54 PNB H. 1- (G-O) Et 1- [1- (PNZ.N =) Et] -3-Pyrd IN > p * 1.-55 PNB H 1- (G-O) Et -CH ₂ CH ₂ NH.PN ₂ and > p 1-56 PNB H 1- (G-O) Et 1-PNZ- 5 -Me ₂ NCO- 3 -Pyrd > p 1-57 PNB H 1- (G-O) Et Tht > p 1-58 PNB H 1- (G-O) Et Et ' > CH (CK ₂ )

ÍJ x

Table 2 <·,

- ‘• s / 4 comb.

C. to R ¹ R ² R ³ R ⁴ X 2-1 1 PNB H 1- (G-O) Et 2- (Et ₂ NCO) Pil > CH (CH) 2 - 2 2 PNB H 1- (G-O) Et 2- ₍₂ NCO Et) Ph > CH (CK ₂ ) 2-3 1 PNB H 1- (G-O) Et 2- [1-Azp.CO] Ph > CH (CH) 2--4 2 PNB ' H ’1- (G-O) Et 2- [1-Azp.CO] Ph > chích ₃ ) 2-5 1 PNB H 1- (G-O) Et 2 -PyrMe > CH (CH) 2-6 2 PNB H 1- (G-O) Et 2 -PyrMe > CH _(CH3) 2-7 1 PNB H 1- (G-O) Et (3-Me-2-Pyr) Me > CH (CH) 2-8 2 PNB H 1- (G-O) Et (3-Me-2-Pyr) Me > CH (CK ₂ ) 2-9 1 PNB H 1- (G-O) Et (1-Me-2-Imide) Me > CH _(CH3) Table 2-10 2 PNB H 1- (G-O) Et (1-Me-2-Im) Me > CH _(CH3) 2-11 1 PNB H 1- (G-O) Et (3-Ithiz) Me . > CH _(CH3) 2-12 2 PNB H 1- (G-O) Et (3-Ithiz) Me > CH (CH ₃ ) 2-13 1 PNB H 1- (G-O) Et 2 - Pyr > CH _(CH3) 2-14 2 PNB Ή 1- (G-O) Et 2-Pyr > CH _(CH3) 2-15 1 PNB H 1- (G-O) Et -CH ₂ CH ₂ NH.PN ₂ > CH _(CH3) 2-16 2 PNB H 1- (G-O) Et -CH ₂ CH ₂ NH.PN ₂ > CH _(CH3) 2-17 1 PNB H 1- (G-O) Et Ph > CH _(CH3) 2-18 2 PNB H 1- (G-O) Et Ph > CH _(CH3) 2-19 1 PNB H 1- (G-O) Et Et > CH _(CH3) 2-20 2 PNB H 1- (G-O) Et Et > CH _(CH3) 2-21 1 PNB H 1- (G-O) Et Bz > CH _(CH3) 2-22 2 PNB H 1- (G-O) Et Bz > CH _(CH3) 2-23 1 PNB H, 1- (G-O) Et -ch ₂ ch ₂ nh.ac > ch ₂ 2-24 1 PNB H 1- (G-O) Et -ch ₂ ch ₂ nh.pnz > CH ₂ 2-25 1 PNB H 1- (G-O) Et -CH ₂ CH ₂ OH > CH ₂ 2-26 and·,·· PNB H 1- (G-O) Et -CH = CH- NH.Ac > CH ₂ - 2-27 1 PNB Formula (1-30) -ch ₂ ch ₂ nh.ac > CH ₂ 2- ⁷ 28 1 PNB H 1-HO-1-MeEt -CH ₂ CH ₂ NH.Ac > CH ₂ 2-29 1 PNB H Et -CH ₂ CH ₂ NH.Ac > CH ₂

Table 2 - cont.

merge

C. & ' R ¹ R ² R ³ R ⁴ X 2-30 1 PNB H 1- (G-O) Et . Ph • r>> ₉ 2-31 1 PNB H 1- (G-O) Et Et > CH 2-32 1 PNB H 1- (G-O) Et Bz > CH ₂ 2-33 1 PNB H 1- (G-O) Et Et > p 2-34 1 PNB H 1- (G-O) Et -ch ₂ ch ₂ nh.pnž > p 2-35 1 All H 1- (G-O) Et 2- ₍₂ NCO Et) Ph > CH _(CH3) 2-36 2 All H 1- (G-O) Et 2- ₍₂ NCO Et) Ph > CH _(CH3) 2-37 1 All H 1- (G-O) Et (3-Me-2-Pyr) Me > CH _(CH3) 2-38 2 All H 1- (G-O) Et (3-Me-2-Pyr) Me CH (.CK ₃ ) 2-39 1 All H 1- (G-O) Et (2-Pyr) Me > CH _(CH3) 2-40 2 All H 1- (G-O) Et (2-Pyr) Me > CH _(CH3) 2-41 1 All H · 1- (G-O) Et 2 -Pyr > CH _(CH3) 2-42 2 All H 1- (G-O) Et 2 - Pyr > CH _(CH3) - 2-43 1 All H 1- (G-O) Et Ph > CH _(CH3) 2-44 2 All H 1- (G-O) Et Ph > CH _(CH3) 2-45 1 All H 1- (G-O) Et Et > CH _(CH3) 2-46 2 All H 1- (G-O) Et Et > CH _(CH3) 2-47 1 All H 1- (G-O) Et Bz > CH _(CH3) 2-48 2 All H 1- (G-O) Et Bz > CH _(CH3)

· .. - / ¾ ř

«4 / i •• 4

Table 3, comp

C. R ⁴¹ R ⁴³ R ¹ R ⁴⁵ R ⁴⁶ and 3-1 TBS H PNB Me Me 0 3-2 'TBS H PNB Me My ^: 1 3-3 TBS H PNB Me Me 2 - -........ ..... 3-4 - TBS -H - PNB '- ...... Et Et 0 3-5 TBS H PNB Et Et 1 3-6 TBS H PNB Et Et 2 3-7 . TBS H PNB Ex Ex 0 ... f A * t. 3-8 TBS H PNB Ex Ex 1 4 »» 3-9 TBS H PNB Ex Ex 2 3-10 TBS H PNB iPr Ex 0 3-11 TBS H PNB ÍPr Ex 1 . /; 3-12 TBS H PNB iPr Ex 2 ϊ · ^; 3-13 TBS H PNB Me Et 0 3-14 TBS H PNB Me Et 1 and 3-15 TBS H PNB Me Et 2 '4 3-16 ’TBS H PNB ÍBu ÍBu 0  and; 3-17 TBS H PNB iBu ÍBu 1 3-18 TBS H PNB ÍBu ÍBu 2 ⁽ Λ 3-19 TBS H PNB Bu Bu 0 C 3-20 TBS H PNB Bu Bu 1 3-21 TBS H PNB Bu · Bu 2 , '3 3-22 TBS H PNB Et Ex 0 jš 3-23 TBS H PNB ' Et Ex 1 '’<4 3-24 TBS H PNB Et Ex 2 3-25 TBS H PNB Me Bu 0 > Ά 3-26 TBS H PNB Me Bu 1 J 3-27 TBS H PNB Me Bu 2 3-28 TMS H PNB Me Me 0

Table 3 - cont.

merge

C. R ⁴¹ R ⁴³ R ¹ R ⁴⁵ R ⁴⁶ t. . and 3-29 TMS H PNB Me Me 1 3-30 TMS H PNB Me Me 2 3-31 TMS H PNB Et Et 0 3-32 TMS  H PNB Et Et 1 3-33 TMS H PNB Et. · Et 2 3-34 TMS H PNB Ex Ex 0 3-35 TMS H PNB Ex Ex 1 3-36 TMS H PNB Ex 'Pr 2 3-37 'TMS H PNB iBu iBu 0 3-38 TMS H PNB iBu iBu 1 3-39 TMS H PNB iBu iBu 2 3-40 TMS H PNB Bu Bu 0 3-41 TMS H PNB Bu Bu 1 3-42 TMS H PNB Bu Bu 2 3-43 TMS H PNB  iPr Et 0 3-44 TMS H PNB iPr Et 1 3-45 TMS H PNB iPr Et 2 3-46 H H PNB Me Me 0 3-47 H H 'PNB Me Me 1 3-48 H H PNB Me Me 2 3-49 H H PNB Et Et 0 3-50 H H PNB Et Et 1 3-51 H H PNB Et Et 2 3-52 H H PNB Ex Ex 0 3-53 H H PNB Ex Ex 1 3-54 ' H H PNB Ex Ex 2 3-55 H H PNB iBu iBu . 0 3-56 H H PNB iBu iBu 1

- 75 Table 3 - cont.

slóuč.

C. R ⁴¹ R ⁴³ . R ¹ R ⁴⁵ R ⁴⁶ and · / 3-57 H H PNB iBu iBu 2 3-58 H. H PNB Bu ' Bu 0 3-59 H H PNB Bu Bu 1 .. 3-60 . H.. . H ~ - ..... PNB Bu - - Bu 2 3-61 H H PNB iPr ’ Et 0 3-62 H H PNB iPr Et 1 3-63 H H PNB iPr Et 2 3-64 H H All Me Me 0 3-65 H H All Me- Me 1 3-66 H H All Me Me 2 3-67 H H All Et Et 0 3-68 H H All Et Et 1 3-69 H H All Et Et 2 3-70 H H All Ex Ex 0 1 3-71 H H All Ex Ex 1 3-72 H H All Ex Ex 2 3-73 H H All ’ iBu iBu 0 ·3 3-74 H H All iBu iBu 1 * » 3-75 H H All ÍBu iBu 2 3-76 H H All Bu Bu 0 '·> 3-77 H H All Bu Bu 1 3-78 H H All Bu Bu 2 3-79 IMS H All Me Me 0 3-80 TMS H All Me Me 1  ’’ J 3-81 TMS H All Me Me 2 ? · 1 * ; /IN 3-82 TMS H All Et Et . 0 3-83 TMS H All Et Et 1 at. 3-84 TMS H All Et . Et 2

- 76 Table 3 - cont.

merge

C. R ⁴¹ R ⁴³ R ¹ R ⁴⁵ . . R ⁴⁶ and • 3-85 TMS H ' All Ex Ex 0 3-86 TMS H All Ex Ex 1 3-87 TMS H All Ex Ex 2 3-88 TMS H All iBu iBu 0 3-89 TMS H All iBu iBu 1 3-90 TMS H All . iBu 'iBu 2 1 3-91 TMS H All Bu Bu 0 •her 3-92 TMS H All Bu Bu 1 3-93 TMS H All Bu Bu 2 3-94 TBS H All Me Me 0 3-95 TBS H All Me - Me 1 3-96 TBS H All Me Me 2 3-97 TBS H All Et Et 0 q 3-98 TBS H All Et Et 1 3-99 TBS H All . Et Et 2 -and 3-100 TBS H All Ex Ex 0 'and 3-101 TBS H All Ex Ex 1 > 1 3-102 TBS H All Ex Ex 2 3-103 TBS H All iBu iBu éř 0 3-104 TBS H All iBu _iBu 1 3-105 TBS H All iBu iBu 2 3-106 TBS H All Bu Bu 0 3-107 TBS H All Bu Bu 1 -AND 3-108 TBS H All Bu Bu 2 Ϊ. 5. 1 3-109 TBS H All Me Et 0  M 3-110 TBS H All Me Et 1 Ί ' 3-111 TBS H All Me Et 2 .. J) 3-112 TMS H All Me Et 0

... <

Table 3 - cont.

merge

; - č. R ⁴¹ R ⁴³ R ¹ R ⁴⁵ R ⁴⁶ and 3-113 TMS H All Me Et 1 « 3-114 . TMS · H All Me Et 2 3-115 H H All Me Et 0 - 3-116 H ....... - ...... H All - Me Et  . 1 3-117 H H All Me Et 2 3-118 H H All Et Ex 0 3-119 H H All Et Ex 1 * 3-120 H H All Et Ex 2 and 3-121 'TMS H All Et Ex 0 3-122 TMS H All Et Ex 1 3-123 TMS H All Et Ex 2 3-124 TBS H All Et Ex 0 3-125 TBS H All Et Ex 1 3-126 TBS H All Et Ex 2 • t ³ - ¹²⁷ TMS H PNB Me Et 0 3-128 TMS H PNB 1 Me Et 1 3-129 TMS H PNB Me Et 2 i Ji 3-130 H H PNB Me Et 0 <»· ! '< 3-131 H H PNB Me Et 1 3-132 H H PNB Me Et 2 <£. · · 3-133 H H PNB Et Ex 0 L * 3-134 H H PNB Et Ex 1 · .4 3-135 H H PNB Et Ex 2 3-136 TMS H · PNB Et . Ex 0 3-137 TMS H PNB Et Ex 1 3-138 TMS  H PNB 'Et Ex 2 .j 3-139 PNZ H PNB Et . Et 0 3-140 PNZ H PNB Et Et 1

and

Table 3 - cont.

merge

C. R ⁴¹ R ⁴³ R ¹ , R ⁴⁵ and .3-141 PNZ H PNB Et Et 2 3-142 PNZ H PNB Me Me 0 3-143 PNZ H PNB Me Me 1 3-144 PNZ H PNB Me Me 2 3-145 PNZ H PNB · iBu iBu 0 3-146 PNZ H PNB iBu · iBu 1

3-147 PNZ H PNB iBu iBu 2 3-148 PNZ H PNB Bu Bu 0 3 -149 'PNZ H PNB Bu Bu 1 3-150 PNZ H PNB Bu Bu 2 3-151 PNZ H PNB Ph Ex 0 3-152 PNZ H PNB Ph Ex 1 3-153 PNZ H PNB Ph Ex 2 3-154 PNZ H All Et Et 0 3-155 PNZ H All Et Et. 1 ΪΪ 3-156 PNZ H All Et Et 2 3-157 TBS H PNB Me Ph 0 1 3-158 TBS H PNB Me Ph 1 3-159 TBS H PNB Me Ph 2 3-160 TMS H PNB Me Ph 0 74 3-161 TMS H PNB Me Ph 1 .4 3-162 TMS H PNB Me Ph 2 . 'F' 3-163 H H PNB Me Ph 0 3-164 H H PNB Me Ph 1 and 3-165 H H PNB Me Ph 2 3-166 TBS . H PNB Et Ph 0 , í 3-167 TBS H PNB Et Ph L Ί 3-168 TBS H PNB Et Ph 2

“I

- 79..Table 3 - cont.

merge R ⁴⁶ and C. R ⁴¹ R ⁴³ R ¹ . . R ⁴⁵ 3-169 TMS. H PNB Et Ph 0 3-170 TMS  H - PNB Et Ph 1 3-171 TMS H PNB Et Ph 2 3-172 H - H '- PNB . Et 'Ph' 0 3-173 H H PNB Et ' Ph 1 3-174 H H PNB Et Ph 2 3-175 TBS 6-Me PNB Et Et 1 3-176 TBS 5-Me PNB. Et Et 1 3-177 'TBS 4-Me PNB Et Et 1 3-178 TBS 5-NO ₂ PNB Ět Et 1 3-179 TBS 5-Cl PNB Et Et 1 3-180 TBS 4-OMe PNB Et Et 1 3-181 TBS 6-Cl PNB Et Et 1 3-182 TBS 3-Me PNB Et Et 1

• i

- 80 Table 4 comp.

C. R ⁴¹ R ⁴³ R ¹ AND and 4-1 TBS H PNB -ICH ₂ ). ₂ -. 0 4-2 TBS H PNB • (ch ₂ ) ₃ - 0 4-3 TBS H PNB • ^(CH2 > 4- 0 4 - 4 TBS H PNB - <ch ₂ ) ₅ - 0 4-5 TBS H PNB - <ch ₂ ) _s -. 0 4-6 TBS H PNB - <ch ₂ ) ₇ - 0 4-7 TBS H PNB - (CH ₂ ) ₂ 0 (CH ₂ ) ₂ - 0 $ with 4-8 TBS H PNB - <c ^h 2) ₂ - 1 . ;} 4-9 ŤBS H PNB - <ch ₂ ) ₃ - . 1 4-10 TBS H PNB - ^(CH 2> 4 ·· 1 4-11. TBS H PNB - ^<CH 2> 5- _; .1 4-12 TBS H PNB - <ch ₂ ) ₆ - 1 , 4-13. TBS H PNB - (¾) ₇ - 1 4-14 TBS H PNB - (CH ₂ ) ₂ O (CH ₂ ) ₂ - 1 J 4-15 TBS H PNB - (¾) ₂ - 2 and 4-16 TBS H PNB - (¾) ₃ - 2 5 4-17 TBS H PNB - V4- 2 4-18 TBS H PNB - (¾) - 2 4-19 TBS H PNB ., ch ₂ : - 2 Ί 4-20 TBS H PNB - < ^ch 2) ₇ . 2 4-21 TBS H PNB - (ch ₂ ) ₂ O (ch ₂ ) ₂ - 2  and 4-22 TMS H PNB - <ch ₂ ) ₂ . 0 * '.1 ^: .T ^' 4-23 TMS H PNB - ^(c h ₂ ) ₃ - 0 4-24 TMS H PNB - < ^ch 2> 4- 0 > J 4-25 IMS H - PNB - ^(CH 2> S- 0 4-26 TMS H PNB • ^ICH 2'S 0 7'3 4-27 '# TMS - H PNB - < ^CH 2> 7 · 0  and 4-28 TMS H PNB - (ch ₂ ) ₂ o (ch ₂ i ₂ - 0

. ji 'j

Table 4 - cont.

merge

C. R ⁴¹ R ⁴³ R ¹ Α -and 4-29 TMS . . Η ΡΝΒ - ( ^CH 2> ₂ - 1 9 ...... 4-3 0 TMS · .. - Η - ΡΝΒ - ^(CH 2> 3- 1 4-31 TMS Η ΡΝΒ 1 ...... ....... 4-32 . TMS Η ΡΝΒ. - (ch ₂ ) ₅ -------- 1 4-33 TMS Η. ΡΝΒ - <ch ₂ , ₆ - · 1 4-34 TMS Η. ΡΝΒ - ^(C 2'7- 1 4-35 TMS Η ΡΝΒ '^ ^CH 2 ^ 2 ° ^ ^CH 2 ^ 2 * 1 F 4-36 TMS Η ΡΝΒ - ^ 2 ^ - 2 i i 4-37 TMS Η ΡΝΒ - (^ 2) 3- 2 4-38 TMS Η ΡΝΒ - ^(CH 2> 4 ^; 2 4-39 TMS Η ΡΝΒ - «: h ₂ ) ₅ - 2 4-40 TMS Η ΡΝΒ - <ch ₂ ) _s - 2 4-41 TMS Η ΡΝΒ '^ ^CH 2 ^ 7' 2 4-42 TMS  Η ΡΝΒ * ^ ^CH 2 ^ 2 ° ^ ^CH 2) 2 ' 2 • .i. 4-43 Η Η ΡΝΒ - ^{CE 2 ^} 2- 0 4-44 Η Η ΡΝΒ - ^{CR 2 ^} 3- 0 4-45 Η Η ΡΝΒ - ^ 2 ^ - 0 ^: · 3 4-46 Η Η ΡΝΒ ₂ ) ₅ - 0 -ί 4-47 Η Η ΡΝΒ - <ch ₂ ) ₆ - 0 • ,, 4-48 Η Η ΡΝΒ ^ ^CIl 2 ^ 7 0 4-49 Η Η ΡΝΒ - (CH ₂ ) ₂ O (CH ₂ ) ₂ - 0 · 4 4-50 Η Η ΡΝΒ - ⁽ CH2'2- 1 - / ’. 4-51 Η Η ΡΝΒ - < ^ch 2> 3- 1 ΐΆ 4-52 Η Η ΡΝΗ • ^(CH2 > 4- 1  Λ 'Λ 4-53 Η Η ΡΝΒ 1 4-54 Η Η ΡΝΒ - ^(CH2 > ₆ - . 1 • ·. · ^: 4-55 Η Η ΡΝΒ - ( ^ch 2) ₇ - 1 4-56 Η Η · ΡΝΒ -CH ₂ ) ₂ O (CH ₂ ) ₂ - 1

Table 4 - cont. merge,

C. R ⁴¹ R ⁴³ R ¹ AND and 4-57 H H PNB 2 4-58 H H PNB - ( _{C 2} ) ₃ - 2 4-59 H H PNB - ^(ch 2) 4 - 2 4-60 H H PNB . - (^ 2) 5- 2 4-61 H H PNB - (¾) ₆ - · 2 4-62 H H PNB '^ ^CI 2 ^ 7' 2 4-63 H H PNB - (CH ₂ ) ₂ O (CH ₂ ) ₂ - 2

a, &

% ·

<· 4-64 H H All - ^(CH 2> 4 · 0 5 4-65 'h H All -, (ch ₂ ) ₅ - 0 4-66 H H All • ^(CH 2's ^: 0 4-67 H H All - <ch ₂ ) _s - 1 4-68 H H All - ^(CH 2> 5- 1 4-69 H H All - ₂ ) ₄ - 1 4-70 H H All - ₍ ch ₂ ) ₄ - 2 '<• ^r 4-71 H. H AU - ( ^c h ₂ ) ₅ - 2  Ί 4-72 ‘H H. All - ( ^c H ₂ ) ₆ - 2 ·, & I 4 4-73 TMS H AU - < ^c h ₂ ) _s - 0 4-74 TMS H All ^(CH 2> 5) 0 and 4-75 TMS H All - < ^ch 2> ₃ - 0 4-76 TMS H All - < ^ch 2) ₄ - 1 4-77 TMS H All - (ch ₂ ) ₅ - 1 4-78 TMS H All - ^their 2'S 1 ...- ¾ ? J 4-79 TMS H All - ^(CH 2> 6- 2 4-80 TMS H All - ^(CH 2> 5- 2 4-81 TMS H All - <ch ₂ ) ₄ - 2 th 4-82 TBS H All - < ^c h ₂ ) ₄ - 0 4-83 'TBS H All - ( ^c h ₂ ) ₅ - 0 * 'Ά4 4-84 TBS H All - ^(CH 2> 6- 0 w ...

Λ

- 83 Table 4 - cont.

merge «41 c. R R ⁴³ R ¹ AND and

4-85 TBS H All - ^(C H _{2) 6} - 1 4 - 86 TBS H All - (c ^h 2) ₅ - - 1 4-87 TBS H All 1 • 4- ⁸⁸ TBS H All - <ch ₂ , ₄ -. 2 4-89 TBS H All - ^(ch 2) ₅ - 2 4-90 TBS H All - < ^ch 2 ^} 6- 2 4-91 PNZ H. PNB - < ^ch 2> 6- 0 $ 4-92 PNZ H PNB -WS- 0 Λ 4-93 'PNZ H PNB -W4- 0 * 4-94 PNZ H PNB '- < ^CH 2> 4- 1 4-95 PNZ H PNB :-( ^CH 2) ₅ - 1. 4-96 PNZ H PNB - ^(CH 2) ₆ - 1 4-97 PNZ H PNB - (C ^ g- 2 4-98 PNZ H PNB - (^ 2) 5- 2 4-99 TBS 4-Me PNB -We- 1 4-100 TBS 5-C1 PNB 1 '  '· #! · 4-101 TBS 5-NO ₂ PNB 1  'íS 4-102 TBS 6-C1 PNB · - ^ 2 ^} 6- 1 > * 4-103 TBS 4-Me PNB - ( ^CH2 ) g- 0 4-104 TBS 5-C1 PNB - ^(CH 2) ₆ - O 4-105 TBS 5-NO ₂ PNB - ( ^CH2 ) g- 0 4-106 TBS 6-C1 PNB - ( ^ch 2) ₆ - 0 4-107 TBS 4-Me PNB - ( ^ch 2) ₆ - 2 • ^s > 4 4-108 TBS 5-C1 PNB - <ch ₂ ) _s - 2 4-109 TBS 5-NO ₂ PNB - (¾) ₆ - 2 Ϊ ’Y ..1, 4-110. .. TBS 6-C1 PNB 2 4-111 TBS 4-Me PNB - ^ÍCH 2 ^} í- 1 . · · * 4-112 TBS 5-C1 PNB - (ce ₂ ) ₄ - 1 ./and 4-113 TBS 5-NO ₂ PNB 1

Of the above compounds, Compounds No. 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7 are preferred compounds,

3-8, 3-9, 3-30, 3-31, 3- 32, 3-33, 3-34, 3-35, .3-36, 3-46, 3-47, 3-49, 3-50, 3-51, 3-52, 3-53, 3-54, 3-64, 3-65, 3-66, 3-68, 3-69, 3-79, 3-80, 3-81, 3-82, 3-33, 3-84, 4-3, 3, 4, 4 -5, 4- 7, 4-10 , 4-11 , 4-12 , 4-14 t • · 4-17, 4-18, 4-19, 4-21 4-24, 4-26, 4-28, 4-31, 4-33, 4-35, 4-38, 4-40, 4-42, 4-45 4-47, 4-49, 4-52, 4-54, 4-56, 4-59,

..and

4-61 and 4-63. More preferred are Compounds No. 3-4,

3-5, 3-6, 3-31, 3-32, 3-33, 3-49, 3-50, 3-51, 4-5, 4-12

4-19> 4-26, 4-33, 4-40, -4-47, 4-54 and 4-61. The most preferred compounds are Compounds No.

4-nitrobenzyl 2- (2-diethylcarbamoylphanylthio) -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate,

4-nitrobenzyl 2- (2-diethylcarboamoylphenyl) sulfinyl) -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate,

4-nitrobenzyl 2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate,

4-nitrobenzyl 2- (2-diethylcarbamoylphenylthio) -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate,

4-nitrobenzyl 2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate,

4-nitrobenzyl 2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate,

3-31.

3-32.

3-33.

3-49,

3-50.

3-51.

4-26. 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylthio] -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate,

4-33. 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylsulfinyl] -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate,

4-40. 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylsulfonyl] -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate,

4-47. 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylthio] -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate,

4-54. 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbobyl) phenylsulfinyl] -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate; and

4-51. 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylsulfonyl] -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate.

In accordance with the present invention, compounds of formula II, which include novel compounds of formula IV, can be converted to the desired compounds of formula I by reaction with a compound of formula III, ASH (as defined above) in the presence of a metal salt. from Group II or III of the Periodic Table.

In the case of metal salts belonging to group II, the metal may be from subgroup A or B. Metals of subgroup A include beryllium, magnesium, calcium, strontium, barium and radium. Group B metals include zinc, cadmium, and mercury, but these are not preferred for use in the method of the invention. Preferred are the metals of subgroup A, magnesium and calcium salts are particularly preferred, and magnesium salts are most preferred. Of these, metal halides such as magnesium chloride, magnesium bromide, magnesium iodide or calcium bromide, a metal-ether complex such as magnesium bromide complex and diethyl ether, a mixture of metal halide or ether complexes with an organic base such as triethylamine, diisopropylethylamine, 1-ethylpiperidine 1,5-diazabicyclo [5.4.0] -5-undecene, 1,4-diazabicyclo [2.2.2-octane] or 1,5-diazabicyclo [4.3.0] nonene, the mixture of which may be prepared, for example, by suspending a Group II metal halide or its ether complex in a solvent, and then adding an organic base (the molar ratio of metal salt to organic base is preferably from 10: 1 to 1.1), a Group II metal amide having the formula IN:

34

R @ 1 R @ 1 .NM - X (V) wherein

Each of R 34 and R independently represents -alkyl groups .. _in a straight or branched chain preferably having 1 to 6, more preferably 1 to 4 carbon atoms such as methyl, ethyl and isopropyl radicals, cycloalkyl preferably having from 3 to 7, more preferably 5 or 6 carbon atoms such as cyclohexyl and cyclopentyl, phenyl or trialkylsilyl, in which each alkyl moiety preferably has from 1 to 6r, more preferably from 1 to 4 carbon atoms, such as trimethylsilyl or R and R together represent a group of formula - in which d is 4 or 5, or a group of formula

- (ch ₂ ) ₂ o (ch ₂ ) ₂ -,

II means a metal belonging to group II and

X represents a halogen atom, such as a chlorine, fluorine or iodine atom, a metal alkoxide belonging to group II and having the formula VI:

R ^35-0 - Μ - X (VI):, 'Ύ. : .d • Ί

Λ

- and in which

R ³ represents a straight or branched chain alkyl group, preferably having from 1 to 6, more preferably from 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl and tert-butyl groups, a cycloalkyl group, preferably having from 3 to 7, more preferably 5 or 6 carbon atoms, such as cyclohexyl and cyclopentyl, or phenyl,

M represents a metal belonging to Group II, and

X represents a halogen atom, such as a chlorine, bromine or iodine atom (a compound of formula VI can be prepared by dissolving a compound of formula R OH in the corresponding solvent used in the reaction and then reacting it with a Grignard reagent such as methylmagnesium bromide or phenylmagnesium bromide); alkali metal such as lithium-

 , '3: 5'

Jt ί ^

2 / ï όή íi

VI bis (trimethylsilyl) amide, lithium diisopropylamide or sodium bis (trimethylsilyl) amide, or an alkali metal alkoxide (such as potassium tert-butoxide or lithium ethoxide) to a metal halide or Group II metal halide ether complex suspended in a solvent to be used for reaction.

In the case of group III of the periodic table, subgroup A comprises scandium, yttrium and lanthanides, but is not certain to be effective in the method of the invention. Group IIIB includes boron, aluminum, gallium, indium, and thallium, and metal salts of this subgroup are preferred, aluminum or boron salts are more preferred, and aluminum is most preferred. Examples of Group III metal salts useful for the reaction include compounds of Formula VII:

R ³³ R ³⁴ N - Ai (R ³⁶ ) ₃ (VII) in which. R and R have a meaning as defined above, and

R ³ represents an alkyl group, preferably having from 1 to 6, more preferably from 1 to 4 carbon atoms, such as methyl or ethyl groups.

Of all the metals of Groups II and III, magnesium, aluminum, beryllium, calcium and boron are preferred.

Of these, magnesium bromide / diethyl ether complex, a mixture of magnesium bromide / diethyl ether complex with diisopropylethylamine, 1-ethylpuperidine or 1,5-diazabicyclo [5.4.0] -5-undecene, bromomagnesiumcyclohexylisopropylamide, bromamagnesiummide magnesium bromide or magnesium bromide is the most preferred. .

Butoxide, a mixture of lithium diisopropylamide or lithiumbistrimethylsilylamide with a magnesium bromide-diethyl ether complex or diethylaluminum diisopropylamide.

There is no particular restriction on the relative amount of reagents and metal salts used: However, it is generally preferred to use a compound of formula II and mercaptan of formula ca III in a molar ratio of from 1: 1 to 1: 3. III is preferably present in an amount of from 1 to 20

- mol per mol of the compound of formula II.

The reaction is usually and preferably carried out in the presence of a solvent, the nature of which is not critical provided that the reaction is carried out

it has no adverse effect on the reaction and that it can at least to some extent dissolve the reactants. Examples of suitable solvents include: hydrocarbons such as cyclohexane, benzene, toluene or xylene, halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons such as methylene chloride, 1,2-dichloroethane or carbon tetrachloride, ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, amides such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidine or hexamethylphosphoric triamide, and sulfoxides such as dimethylsulfoxide. Of these, hydrocarbons, halogenated hydrocarbons, ethers or amides are preferred, ethers being particularly preferred.

The reaction will take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature in the range of -70 to 60 ° C, more preferably from 0 to 30 ° C. The time required for the reaction may similarly vary widely depending on many factors, particularly the reaction temperature and the nature of the components. In most cases, however, a sufficient period of from 10 minutes to 48 hours will be sufficient when sulfinyl derivatives are used, and from 10 minutes to 90 minutes it will be sufficient if sulfonyl derivatives are used.

Sulfinyl derivatives of formula IX or sulfonyl derivatives of formula X, which may be used as starting material for this reaction, may be synthesized by oxidation of a compound of formula XI according to a known method using a suitable oxidizing agent, for example peroxide, such as butyl peroxide as shown in Reaction Scheme 2 below:

^r ·· ^

(X)

'TO; ->

3 4

In the above formulas R, R, R and R are as defined above.

When tert-butyl peroxide is used, it is preferred to use it as a catalyst of vanadylacetylacstonate έ

A-91 (WO (acac) ₂ ). In addition to removing any peroxide-derived acidic substances formed in this reaction, the oxidation reaction is preferably carried out in the presence of a base such as an alkali metal carbonate or an aqueous solution thereof.

The sulfone derivatives of formula X may be synthesized either by further oxidation of the sulfinyl derivatives of formula IX according to the above method or by direct oxidation of a compound of formula XI.

These oxidation reactions are described in more detail in relation to step 3d of Reaction Scheme 3.

^f A compound of formula XI, used as starting material may be synthesized from a natural substance when X represents CH ^ (e.g., as described in Schmitt SM and others,

J. Org. Chem., 1980, 45, 1142) or according to said method. when X is Cl 2 or CH 2 CH 2), for example as described

S. Oida et al., Tetrahedron Letters, 25, 2793 (1984); and B. G. Christensen et al., Heterocycles, 21, 29 (1984).

when X in the compound of formula XI is a sulfur atom, the compound can be synthesized, for example, according to the following method of S. Oida et al., Chem. Pharm. Bull., 29, 3158 (1981); A. Yoshida et al., Chem. Pharm. Bull., 31, 768 (1983).

Preferred examples of compounds of formula ASH (III) used in the invention are compounds of formulas IIIa to IIIf.

IH (IHa)

COŇMe, • 5

HS

(nothing)

PNZ (DLB)

N — PNZ

N — PNZ (md)

The compound of formula I obtainable by the process of the invention can be converted to = the corresponding carbapenem or penem derivative having excellent antibacterial effects, removal of the carboxy protecting group and, in some cases, removal of the hydroxy protecting group R and R at the 6a position of any protecting group in A means.

The compounds of formula IV of the invention may be prepared, for example, as outlined in the following Reaction Scheme 3:

R ^J 5 ✓

^S R46 oo, if ii.

R'O-C-C-Cl step 3a ^(ΧΙΠ)! * i

M

?>

Grade 3b

R ^{4 S} P (R ⁴ 9) ₂ (XV) grade 3c

• i £ * ii

41 42 43

In the above formulas R, R, R, R, R,

R and Y are as defined above.

R ⁴⁸ represents an alkyl group having from 1 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms.

χ.

Where R is an alkyl group having from 1 to 6 carbon atoms, it may be, for example, any of the groups exemplified in relation to R1, in particular methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

When R represents an alkoxy group having from 1 to 6 carbon atoms, it may be, for example, any of the above-mentioned groups in relation to R, in particular methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy- or a target. .butoxy.

R represents an alkoxy group having from 1 to 6 carbon atoms or an aryloxy group in which the aryl moiety may have the meaning as generally defined above and the examples given.

When R is alkoxy, it may be the same alkoxy as defined and the examples given when R is aryloxy may be, for example, phenoxy, 4-methylphenoxy or 4-methoxyphenoxy.

j is 1 or 2.

*

The compound of formula XII in which R represents terc.butyl42 dimethylsilyl group, R is a methyl group, a group of formula -C (= Y) NR ⁴⁵ R 46 _represents the formula _nu i _sRup -CONEtna second position, and R is hydrogen (Japanese discovered

Patent Application No. Hei 4-174099), which can be used as a starting material in Reaction Scheme 3, can be prepared by reacting Z (O) -1-tert-butyldimethylsilyloxy-1- (diethylcarbamoylphenylthio) -1-propene with ( 3R, 4R) -3 - [(R) - (tert-Butyldimethylsilyloxy) ethyl] -4-acetoxyazetidinone, and is obtained in 77% yield. It can only be purified by recrystallization without column chromatography. Accordingly, this compound is a valuable intermediate in the industrial production of 1-beta-methylcarbapenem derivatives.

Reaction Scheme 3 involves the preparation of a compound of formula IVa by reacting a compound of formula XII with an acid chloride of formula XIII to produce an N-oxalyl derivative of formula * XIV and then treating the product with phosphoric acid triester ⁵ or phosphoric diester. The reaction can be carried out by the well known methods described in Tetrahedron Letters, 25, 2793 (1984) or in the Japanese patent application. No. Hei 4-180779.

Stage 3a:

u • i

The compound of formula XIV can be produced by introducing into a compound of formula XIV; reacting a compound of formula XII with an acid chloride of formula

I XIII in the presence of the principle. It is preferred to use from 2 to equivalents of the acid chloride of formula XIII per equivalent Ί of the compound of formula XII.

i ·.

There is no particular restriction on the nature of the principle, provided that it has no adverse effect on the reaction.

; Examples of suitable bases include cyclic or linear tertiary amines such as diisopropylethylamine, diisopropylmethyl | amine, triethylamine, 1-ethylpiperidine, 1-methylmorpholine, 1i) -ethylpyrrolidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diaza, [eta] &lt; 5 &gt; bicyclo [5.4.0] undec-5-ene or 1,5-diazabicyclo [4.3.0] non-5-ene.

 and

The reaction is conveniently and conveniently carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons, such as methylene chloride, chloroform or dichloroethane, ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, especially aromatic hydrocarbons, such as benzene or. toluene, and nitriles such as acetonitrile or propionitrile.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature of from -78 to 50 ° C, more preferably from -30 to 30 ° C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 5 minutes to 3 hours will usually suffice.

Upon completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means and then, if necessary, by quenching any excess of the acid halide with the alcohol. An example of such one method is: adding water to the reaction mixture, extracting the desired compound of formula XIV with a water insoluble organic solvent such as said reaction solvent or ethyl acetate, and distilling off the solvent from the extract. The compound thus obtained can, if desired, be purified by conventional means, such as column chromatography.

the phosphorus compound XV and its oxygen adduct under reduced pressure, or by precipitating the product by adding a nonpolar solvent such as hexane to the reaction mixture.

The crude product of formula XVI thus obtained can be used in the next step without any purification. However, the product can, if desired, be purified by conventional means, such as column chromatography.

Stage 3c:

The compound of formula IVa can be produced by heating a phosphate of formula XVI.

The reaction is conveniently and conveniently carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved, and that it can dissolve the reagents, at least to some extent. Examples of solvents include substituted aromatic hydrocarbons such as toluene, xylene, mesitylene, or chlorobenzene.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. Generally it is

...? convenient to carry out the reaction at a temperature of from 100 to 200 ° C, more preferably from ³ 120 to 170 ° C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the solvent and reagents employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 1 to 30 hours will usually suffice.

After completion of the reaction, the product of formula IVa can be obtained from the reaction mixture by distilling off the solvent and recrystallizing or chromatographing the residue.

-100 Grade 3d:

This optional step for producing a compound of Formula Ib involves oxidizing a compound of Formula IVa.

The S-oxide compound of formula IVb can be produced by reacting a compound of formula IVa with an oxidizing agent. Examples of fog oxidizing agents include: peroxides, such as 3-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide, or tert-butyl peroxide. When tert-butyl peroxide is used as the oxidizing agent in this reaction, the reaction is preferably carried out in the presence of a catalyst such as vanadylacetylacetonate or molybdenylacetylacetonate, preferably vanadylacetonate. In order to remove any acidic component derived from such oxidizing agents during the reaction, the oxidation reaction may take place in the presence of a base such as an alkali metal carbonate or an aqueous solution thereof.

The reaction is conveniently and conveniently carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include alcohols such as methanol or ethanol, halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons such as methylene chloride, chloroform or 1,2-dichloroethane, of which halogenated hydrocarbons are preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it has been found convenient to carry out the reaction at a temperature of from -10 to 50 ° C, more preferably from 0 to 25 ° C.

The reaction may also vary widely depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 6 hours will suffice.

After completion of the reaction, the compound of formula IVb can be recovered from the reaction mixture by the following methods: any excess oxidizing agent is quenched by the addition of 10% aqueous sodium sulfite solution and then the reaction mixture is diluted with a solvent such as methylene chloride, washed with water and dried.

The resulting residue can be purified by conventional means, such as recrystallization or chromatography, to give the compound of formula IVb.

Either a sulfinyl compound of formula j IVb (j * is 1) or a sulfonyl compound of formula IVb

Λ (j 'is 2) by varying the amount of oxidizing agent. Excess oxidizing agent will facilitate the production of the compound wherein i 'is 2.

^: á

Alternatively, a compound wherein j * is 2 can be prepared by oxidizing the corresponding compound wherein j 'is 1, using the same method ^. Conditions such as those described above.

If, after completion of these reactions, the hydroxy protecting group represented by R in any of the compounds of formula IVa or IVb may be deprotected.

AND-

This is accomplished using the well known method described in T. W.

Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, Inc., 1991, p. 10, 2nd edition.

The invention is further illustrated by the following non-limiting examples. The following are used in the example samples

abbreviations: Et: ethyl group Me: methyl group PNB: 4-nitrobenzyl PNJZ: 4-nitrobenzyloxycarbonyl group TMS: trimethylsilyl group TBS: a tert-butyldimethylsilyl group.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-nitrobenzyl- (1R, 5S, 6S) -2 - [(3S, 5S) -5-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -3-pyrrolidinylthio] -1-methyl-6- / 1 (R) - trimethylsilyloxyethyl -1-carbapen-2-em-3-carboxylate

OTMS

I t

CH,

H, C

COOPNB

PNZ

CONMe, ml of tetrahydrofuran solution containing 68 mg, 0.19 mmol of (2S, 4S) -2-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine was cooled in an ice bath, then 0 was added dropwise over 2 minutes , 19 mL, 0.19 mmol of a 1M tetrahydrofuran solution of bromomagnesium-N-isopropyl-N-cyclohexylamide. The mixture was an additional 10 minutes

The mixture was stirred at the same temperature, and then 1 ml of tetrahydrofuran solution containing 100 mg of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- / 1 ( R) -trimethylsilyloxyethyl] -1-carbapen-2-em-3-carboxylate, prepared as described in Example 21. The mixture was stirred for an additional 15 minutes at the same temperature, then ice water was added. The reaction solution was then diluted with ethyl acetate, washed with aqueous ammonium chloride, and then with saturated aqueous sodium chloride. The solvent was removed by distillation under reduced pressure and the resulting residue was purified by column chromatography on 10 g silica gel, eluting with ethyl acetate, to give 94 mg (yield 78%) of the title compound as a foamy solid.

IR spectrum (liquid film), in cm max

1773, 1711, 1655, 1522, 1345, 1142, 845.

NMR Spectrum (CDCl3, 270 MHz) [delta] ppm:

(4.5H, singlet), (4.5H, singlet),

- 1.29 (6H, multiplet),

- 2.00 (1H, multiplet),

- 2.80 (1H, multiplet), (1.5H, singlet), (1.5H, singlet), (1.5H, singlet), (1.5H, singlet),

- 3.27 (1H, multiplet),

- 3.40 (1H, multiplet), - 3.57 (1H, multiplet),

- 3.76 (1H, multiplet),

- 4.30 (3H, multiplet), (0.5H, triplet, J = 8Hz), (0.5H, triplet, J = 8Hz),

0.13 0.14 1.25 1.89 2.67 2.94

2.98

3.00

Vij

3.11 ~ 3.22

3.30 3.46 / 4 · * g 3.60

4.02 4.72 •• 1 4.76 β’ΐ

- 104 -

5,07 (0.5H, doublet, J = 14 Hz). 5.22 (1H, singlet) 5.25 (1H, doublet, J = 14 Hz), 5.30 (0.5H, doublet, J = 14 Hz), 5.46 (1H, doublet, J = 14 Hz), 7.44 (1H, doublet, J = 9 Hz), 7.52 (1H, doublet, J = 9 Hz), 7.65 (2H, doublet, J = 9 Hz), 8.20. (1H, doublet, J = 9 Hz), 8.21 (3H, doublet, J = 9 Hz). Mass spectrum (m / z) • 754/14

Example 2

4-nitrobenzyl- (1R, 5S, 6S) -2 - [(2S, 4S) -2-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio] -1-methyl-6- / 1 (R) - tert-butyldimethylsulyloxyethyl] -1-carbapen-2-em-3-carboxylate

a) The following procedure is the same as that described in Example 1, but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2H-diethylcarbamoylphenylsulfinyl) -1-methyl-6- / 1 (R) -ter. 1-carbapen-2-em-3-carboxylate, prepared as described in Example 22. The resulting compound was obtained as a pan-like solid with a yield of 86%.

- 105

b) By the method of Example 1, but using 4-nitrobenzyl (1R, 5S, 6S) -2- [2- (2H-1,3,4,5,6,7-hexahydro-1-azepinyl) carbonylphenylsulfinyl] - 1-methyl-67/1 (R) -ter. Butyldimethylsilyloxyethyl-1-carbapen-2-era-3-carboxylate obtained according to Example 24 gave the product as a foamy substance, yield 83%.

c) 25 microliters, 0.144 mmol of diisopropylethylamine was added to 2 ml of tetrahydrofuran suspension containing 50 mg, 0.071 mmol of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- / 1 (R) tert-Butyldimethylsilyloxyethyl-1-carbapen-2-em-3-carboxylate, prepared as described in Example 25, 30 mg, 0.086 mmol of (2S, 4S) -dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4- mercaptopyrrolidine and 76 mg, 0.294 mmol of magnesium bromide-diethyl ether complex. The resulting suspension was then stirred for 94 hours. At the end of this time, the reaction solution was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution. The solvent was removed by distillation under reduced pressure and the resulting residue was purified by silica gel column chromatography using a 1: 1 by volume mixture of methylene chloride and ethyl acetate as eluent to give 40 mg (yield 69%) of the title compound as a pan-solid.

d) The following procedure is the same as that described in p

and Example 1, but using 76 mg of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- [1 (R) -ter. butyldimethylsilyloxyethyl 1-carbapen-2-em-3-carboxylate, prepared as described in Example 25, and 46 mg of (2S, 4S) -dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine. The resulting compound was obtained in a yield of 78%.

.-4 «Ί

e) The following procedure is the same as that described in Example 1, but using 101 mg of 4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2-] 2- (4'-nitrobenzyloxycarbonyl-aminoethylsulfinyl) -1-carbapen-2-emine-3-carboxylate, prepared as described in Preparation 5a mg of (2S, 4S) -dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine. The resulting compound was obtained'a: 83% yield "

106 f) The following procedure is the same as that described in Example 1, but 100 mg of 4-nitrobenzyl (1R, 5S, 6S) -6 = [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2-ethylsulfinyl- 1-methyl-1-carbapen-2-em-3-carboxylate, prepared as described in Preparation 6, was reacted with 79 mg of (2S, 4S) -dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine . The product was purified by silica gel column chromatography using ethyl acetate as eluent to give a fraction containing the title compound in a yield of 87%. This fraction, which contains impurities that cannot be separated by silica gel column chromatography, showed a purity of 83.5% as determined by the liquid chromatography area ratio.

g) 75 microliters of hexane containing 1.6 M butyllithium was added to 1 ml of an ice-cooled toluene solution containing 18 microliters, 0.13 mmol of diisopropylamine and stirred for 10 minutes. At the end of this time was added

125 microliters, 0.12 mmol of a hexane solution containing 0.97 M diethylaluminum chloride and the mixture was stirred at the same temperature for a further 20 minutes. The diethylaluminum diisopropylamide solution thus obtained was added to a 2 ml ice-cooled tetrahydrofuran solution containing 43 mg, 0.12 mmol of (2S, 4S) -dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine and stirred at the same temperature for 15 minutes. At the end of this time, 1 ml of tetrahydrofuran solution containing 68 mg, 0.10 mmol of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- / 1 (R) - was added. tert-Butyldimethylsilyloxyethyl] -1-carbapen-2-em-3-carboxylate, prepared as described in Example 22, to the reaction mixture and stirred for 105 minutes. Saturated aqueous ammonium chloride solution was added followed by ethyl acetate. The compound that formed was removed. The organic layer was separated and washed with water and then with a saturated aqueous sodium chloride solution. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography on 10 g silica gel, using a 1: 3 by volume mixture of benzene and ethyl acetate as eluent, to give 60 mg of the fraction containing the title compound in 74% yield. This fraction showed a purity of 56% as determined by area ratio according to liquid chromatography.

The properties of the title compound obtained in a) to g) are described below.

IR spectrum (liquid film) in _max cm:

1775 1713 1657, 1522, 1345, 1142, 837 • NMR-1 spectrum (CDCl 3, 270 MHz) ppm: 0.07 - 0,09 (6H, multiplet) 0.85 (4.5H, singlet), 0.87 (4.5H, singlet), 1,23 - 1,29 (6H, multiplet) 1.88 - 2,00 (1H, multiplet). 2.67 - 2,81 (1H, multiplet) and 2.94 (1.5H, singlet), 2.98 (1 / 6H, singlet), 2.99 (1.5H, singlet), 3.11 (1.5H, singlet), 3.23 - 3,41 (2H, multiplet) 3.46 - 3,57 (1H, multiplet) * $ 3.61 - 3,78 (1H, multiplet) 4.03 - 4,32 (3H, multiplet) 4.73 (0.5H, triplet, J = 8Hz) 4.77 (0.5H, triplet, J = 8Hz) ÍÝ _; 5,07 (0.5H, doublet, J = 13 Hz), 5.22 (1H, singlet)

108

5.25 (1H, doublet, J = 13 Hz) 5.30 (0.5H, doublet, J = 13Hz 5.45 (1H, doublet, J = 13 Hz) 7.45 (1H, doublet, J = 9 Hz) 7.52 (1H, doublet, J = 9 Hz) 7.65 (2H, doublet, J = 9 Hz) 8.20 (1H, doublet, J = 9 Hz) 8.21 (3H, doublet, J = 9 Hz)

Mass spectrum (m / z): 754 (M ⁺ ( ^C 33 ^H 49 ^N 5 ^N 5 ^{SS 3} · ^-C 4 ^H 9)

Example 3

4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2 - [(2S, 4S) -2-] - 4- (2- (4-nitrobenzyloxycarbonyloxy) ) ethyl (piperazin-1-ylcarbonyl) -1- [(4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio] -1-carbapen-2-em-3-carboxylate

O PNZ

(a) The following procedure is the same as that described in

Τ '* Example 1, but using 4-nitrobenzyl (1R, 5S, 6S) -2- ^({2, -diethylkarbamoylfenylsulfinyl) -l-methyl-6- / l (R) -t-butyldimethylsilyloxyethyl / -l-carbapen -2-em-3-carboxylate, prepared as described in Example 22 and (2S, 4S) -4-mer. / kapto-2- / 4- / 2- (4-nitrobenzyloxycarbonyloxy) ethyl / piperazine109

-1-ylcarbonyl / -1- (4-nitrobenzyloxycarbonyl) pyrrolidine starting materials in relative proportions as used in the example. The title compound was obtained in a yield of 86%. Recrystallization of this product from toluene gave crystals melting at 134-136 ° C.

b) The following procedure is the same as that described in the example. 2c) but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-carbapen-2-em-3- a carboxylate prepared as described in Example 25, and (2S, 4S) -4-mercapto-2- [4- [2- (4-nitrobenzyloxycarbonyloxy) ethyl] piperazin-1-ylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidine starting materials in the same proportions as used in the present example. The title compound was obtained in 60% yield.

IR spectrum (KBr), ν, cm max

1773, 1750, 1709, 1653, 1522, 1345, 1260, 1146, 837.

^L <

_r NMR Spectrum (CDCl3, 270 MHz) C ppm:

and

0.06 - 0.09 (5H, multiplet)

0.85 (4.5H, singlet), 0.86 (4.5H, singlet), 1.22-1.29 (6H, multiplet),

1.84 - 1.99 (1H, multiplet)!

2.38 - 2.81 (7H, multiplet),

3.23 - 3.77 (8H, multiplet), * 4.04-4.32 (5H, multiplet), and 4.73 (1H, doublet of triplets, J = 14 and 8 Hz)

5.07 (0.5H, doublet, J = 14 Hz),

I; 5.22 (1H, singlet).

5.26 (2H, singlet),

110 -

5.25 (1 H, doublet, J = 14Hz) 5.30 (0.5H, doublet, J = 14 Hz) 5.45 (1 H, doublet, J = 14Hz) 7.44 (1 H, doublet. J = 9 Hz) 7.52 (1 H, doublet, J = 9 Hz) 7.56 (2H, doublet. J = 9 Hz) 7.65 (2H, doublet, J = 9 Hz) 8.17 - 8% 26 (6H, multiplet).

Example 4.

4-Nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -t-butyldimethylsilyloxyethyl] -1-methyl-2- / 1 (S) - [N- (4-nitrobenzyloxycarbonyl) acetimidoyl] pyrrolidin-3 -ylthio] -1-carbapen-2-em-3-carboxylate

CH ₃

a) The following procedure is the same as that described in Example 1, but using 4-nitrobenzyl (1R, 5R, 6S) -2 (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- (1 (R) -t-butyldimethylsilyloxyethyl) 1-carbapen-2-em-3-carboxylate, prepared as described in Example 22 and (S) -3-mercapto-1- [N- (4-nitrobenzyloxycarbonyl) acetimidoyl] pyrrolidine as starting material, in ratios the same as used in this example. The title compound was obtained with a yield of 79%. Recrystallization from a mixture of diisopropyl ether and ethyl acetate yielded the crystals melting at 171-172.5 ° C.

b) 4 ml of a tetrahydrofuran suspension containing 101 mg, 0.148 mmol of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-dimethylcarbamoylphenylsulfinyl) -1-methyl-6- [1- (R) -tert-butyldimethylsilyloxyethyl] -1- carbapen-2-em-3-carboxylate, prepared as described in Example 22, 106 mg, 0.328 mmol of (S) -3-mercapto-1- [N- (4-nitrobenzyloxycarbonyl) acetimidoyl] pyrrolidine and 155 mg, 0.600 mmol of magnesium bromide-diethyl ether complex was stirred for 6 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, washed with water and then with a saturated aqueous sodium chloride solution. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (5 g). The title compound containing a small amount of impurities was obtained by eluting with a 1: 1 by volume mixture of hexane and ethyl acetate. This impure compound was purified by subsequent chromatography on -5 g silica gel eluting with a 1: 3 by volume mixture of ethyl acetate and methylene chloride to afford 74 mg (yield 64%) of the title compound.

c) The following procedure is the same as that described in Example 2c) but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenoxysulfonyl) -1-methyl-6- / 1 (R) -ter. butyldimethylsilyloxyethyl] -1-carbapen-2-em-3-carboxylate, prepared as described in Example 25, and (S) -3-mercapto-1- [N- (4-nitrobenzyloxycarbonyl) acetimidoyl] pyrrolidine starting material in proportions the same amount as used in this example. The title compound was obtained in 39% yield.

112

IR-spectrum (KBr), in cm-1:

max

1769, 1694, 1675, 1567, 1520, 1345, 1242, 839.

NMR Spectrum (CDCl3, 270 MHz) .delta. Ppm:

1 Á 0.08 (3H singlet) 0.09 (3H singlet) Zi * - 0.87 (9H singlet) IN 1,22 - 1 ', 31 (6H, multiplet) 1.96 - 2.16 (1H, multiplet), 2.29 (0.75H, singlet), 2.32 (2.25H, singlet), 2.35 - 2.51 (1H, multiplet), • -Ι-- -fe 3.23 - 3.35 (2H, multiplet), fez 3.44 - 4.05 (5H, multiplet), ífez. 4.24 - 4.32 (2H, multiplet), 5.22 (2H, singlet), z ™, ....., 5.24 (1H, doublet, J = 14Hz) 3fcXXX. 5.45 (1H, doublet, J = 14Hz) 5s - .y 7.56 (2H, doublet, j = 9Hz), 7.65 (2H, doublet, J = 9Hz),  Ϊ 8.19 (2H, doublet, J = 9Hz),  X <i WITH 8.21 (2H, doublet, J = 9Hz).

Mass spectrum (m / z): 781 (M ⁺ , ^C 37 ^H 47 ^N 5 ° iq ^s ) »

Example 5

4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2- [2- (4-nitrobenzyloxycarbonyl) aminoethylthio] -1-carbapen-2-em-3 -carboxylate or '» ^: Ξ ~ ·

113

a) The following procedure is the same as that described in Example 1, but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- / 1 (R) - target. either dimethylsilyl oxyl ethyl / 1-carbapen-2-em-3-carboxylate, prepared as described in Example 22, and 2- (4-nitro-benzyloxycarbonyl) aminomethylmercaptan starting materials in proportions equal to used in; this example. The title compound was obtained as a foamy solid in 92% yield.

i · ''. '.

;; b) Following a procedure similar to that described in Preparation ¹ clade 4b), but using 4-nitrobenzyl (IR, 5S, 6S ~} -2- (2J -difenyIkarbamoylfenylsulf ynyl) -1-methy1-6- / 1 (R (bull tyldimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate, prepared as described in Example 22, and 2- (4-nitro-benzyloxycarbonyl) aminoethyl mercaptan starting materials in proportional amounts as used herein The title compound was obtained in a yield of 83%.

and

c) The following procedure is the same as described in Example 4b) but using the lower polarity S-oxide isomer of 4-nitrobenzyl (1R, 5S, 6S) -6- (1) (t-butyldimethylsilyloxyethyl) -1- methyl 2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate, prepared as described in Preparation 2, and 2- (4-nitro) -2- (4-nitro) -2- (4-nitro) -2- (4-nitro) -2- (4-nitro) -2- (2-phenylsulfinyl) -1-carbapen-2-em-3-carboxylate; and

114benzyloxycarbonyl) aminoethyl mercaptan starting materials in a proportional amount to that used in this example. The title compound was obtained in 81% yield.

d) Following the same procedure as described in c) above, the corresponding higher polarity S-oxide is used. The title compound was obtained in 89% yield.

e) The following procedure is the same as that described in Example 2c), but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- / 1 (R) -ter. butyldimethylsilyloxyethyl -1-carbapen-2-em-3-carboxylate, prepared as described in Example 25, and 2- (4-nitrobenzyloxycarbonyl) aminoethyl mercaptan as starting materials, in proportional amounts as described in this Example. The title compound was obtained in 87% yield.

f) The following procedure is the same as described in Example 2c) but using 4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -t-butyldimethylsilyloxyethyl] -1-methyl-2-phenylsulfonyl-1 -carbapen-2-em-3-carboxylate, prepared as described in Preparation 3, and 2- (4-nitrobenzyloxycarbonyl) aminoethyl mercaptan as starting materials in a relative ratio as used in this Example, the title compound was obtained in a yield of 86 %.

g) 0.14 ml, 0.21 mmol of a cyclohexane solution containing 1.5M lithium diisopropylamide-tetrahydrofuran complex was added to a 2 ml ice-cooled tetrahydrofuran suspension containing 91 mg, 0.352 mmol of magnesium bromide-diethyl ether complex. The resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time, 2 mL of a tetrahydrofuran solution containing 55 mg, 0.207 mmol was added

115 2- (4-nitrobenzyloxycarbonyl) aminoethyl mercaptan to the mixture, which was then stirred for an additional 10 minutes in an ice bath.

102 mg, 0.174 mmol of the lower polarity S-oxide isomer,

4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate, prepared as described in Preparation 2 was added to the mixture and stirred for an additional 15 minutes. At the end of this time, a saturated aqueous solution of% ammonium chloride was added, and then the mixture was extracted with ethyl acetate. The resulting organic extract was washed first with water and then with a saturated aqueous sodium chloride solution, then the solvent was removed by distillation under reduced pressure. The rest was ... or a puppy ... chromatography on. 15 g column of silica gel using a 1: 19 volume mixture of ethyl acetate and hexane as eluent to give 104 mg (yield 84%) of the title compound as a foamy solid.

IR-spectrum (liquid film), in cm -1 max

1771, 1723, 1607, 1522, .1347, 1140.

NMR Spectrum (CDCl270 MHz) δ ppm:

0.07 (3H, singlet);

0.08 (3H, singlet),

0.86 (9H, singlet);

1.22 - 1.28 (6H, multiplet)

2.93 (1H, doublet) triplets, J = 13 and 7 Hz), ,in 3.11 (1H, doublet) triplets, J = 13 and 7 Hz), F . * .1 'i 3.26 (1H, doublet) doublets, J = = 3 a 5 Hz), ýr 3.30 - 3.60 (3 H, multiplet) 4.22 - 4.31 (2H, multiplet)

M 5.20 (2H, singlet).

; 5.25 (1H, doublet, J = 14Hz),

5.35 (1H, indistinct triplet, J = 6 Hz),

5.47 (1H, doublet, J = 14Hz) 7.50 (2H, doublet, J = 9 Hz), 7.66 (2H, doublet, J = 9 Hz), 8.20 (2H, doublet, J = 9 Hz), 8.21. (2H, doublet, J = 9 Hz).

Mass spectrum (m / z): 714 (M ⁺ , C ⁺ _O OH .ΝΟS).

, 3342410 · ..

Example 6

4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxy ethyl] -1-methyl-1- (4-nitrobenzylthio) -1-carbapen-2-em-3-carboxylate

a) The following procedure is the same as described in Example 1, but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- [1 (R) -tert-butylsilyloxyethyl 1-carbapen-2-em-3-carboxylate, prepared as described in Example 22, and 4-nitrobenzyl mercaptan as starting materials, in proportional amounts as used in this Example. The title compound was obtained in 81% yield. Recrystallization of this product from a mixture of ethyl acetate and diisopropyl ether gave the title compound as crystals melting at 150.5-151 ° C.

117

b) The following procedure is the same as described in Example 4b) but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- / 1 (R) -ter. butyldimethylsilyloxyethyl -1-carbapen-2-em-carboxylate, prepared as described in Example 22, and 4-nitrobenzyl mercaptan as starting material in a proportional amount to that used in this Example. The title compound was obtained in 38% yield.

IR spectrum (XBr), cm:

. max

1773, 1711, 1605, 1522, 1345, 1140.

f. NMR spectrum (CDCl3, 270 MHz) r) ppm:

0.06 (3H, singlet), 0.08 (3H, singlet), ³ 0.85 (9H, singlet), ..4 1.24 (3H, doublet, J = 5 Hz), and. 1.26 (3H, doublet, J - 6 Hz), • 3.25 (1H, doublet, doublets, J = 2 a 5 Hz '), and- 3.30 (1H, doublet of quartets, J = 10 and 6 Hz), .-¾ 4,11 - 4, 23 (3H, multiplet) 4.25 (IR, quintet, J = 5 Hz), 5.25 (1H, doublet, J = 14 Hz), 5.4 6 (1H, doublet, J = 14 Hz), Me 7.52 (2H, doublet, J = 8 Hz), Ř 4 '  and and 7.65 (2H, doublet, J = 8 Hz), 8.20 (2H, doublet, J = 8 Hz), -4 8.21 (2H, doublet, J = 8 Hz).

Mass spectrum (m / z): 627 (M ⁺ , C 19 H 18 N 2 O 5 SSi).

- 'í

AND

'.φν' _: · '·'>'Τ'! · '- · * ·' --Λ ''

118 Example 7

4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxy ethyl] -1-methyl-2-phenylthio-1-carbapen-2-em-3-carboxylate

Mr ',.

The following procedure is the same as that described in Example 4b) but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- / 1 (R) -tert-butyldimethylsilyloxyethyl 1-carbapen-2-em-3-carboxylate prepared as described in Example 22 and thiophenol starting materials in a proportional amount to that used in this Example. The title compound was obtained as crystals in a yield of 72%. Recrystallization of the product from ethyl acetate / hexane gave crystals of the title compound melting at 149-150 ° C.

IR spectrum (KBr), cm @ -1:

max

1768, 1694, 1607, 1335, 1136, 839.

• í \ rt

NMR Spectrum (CDCl3, 270 MHz)

0.06 (6H, singlet), 0.84 (9H, singlet), 0.95 (3H, doublet, J - Ί Hz), 1.17 (3H, doublet, J = 6 Hz),

. -4 ppm:

ι

119 -

3.06 (1H, doublet quartets, J = 10 a 7 Hz) 3.19 (1H, doublet doublet, J = 2 and 5 Hz), 4.19 (1H, doublet doublets, J = 2 and 10 Hz), 4.25 (1H, doublet quartets, J = 5 and 6 Hz), 5.33 (1H, doublet , J = 14Hz), 5.50 (1H, doublet , J = 14Hz),

7.37 - 7.43 (3H, multiplet), 7.51 - 7.57 (2H, multiplet), 7.69 (2H, doublet, J = 8 Hz), 8.22 (2H, doublet, J = 8 Hz).

Mass spectrum (m / z)

Example 8

563 (M ^{+ C} 29 ^H 36 ^N 2 ° 6 ^SSI )

4-nitrobenzyl (1R, 5S, 6S) -2- [2- (1-perhydroazapinylcarbonyl) phenylthio] -1-methyl-6- [1- (R) -tert-butyldimethylsilyloxyatyl] -1-carbapen-2-em -3-carboxylate

r

The following procedure is the same as that described in Example 1, but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- / 1 (R) -tert-butyldimethylsilyloxyethyl 1-carbapen-2-em-3-carboxylate, prep

and

120, as described in Example 22, and 2- (1-perhydroazepinylcarbonyphenylmercaptan as starting material, in a proportional amount to that used in this Example. The title compound was obtained in a yield of 95%. as described in Example 19 and that it has the same physical and chemical properties.

Example 9

4-Nitrobenzyl (1R, 5S, 6S) -5- [1 (R) -tert-butyldimethylsilyloxy ethyl] -2-ethylthio-1-methyl-1-carbapen-2-em-3-carboxylate.

The following procedure is the same as described in Example 1, but using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- (1 (R) -tert-butyldimethylsilyloxyethyl) - 1-carbapen-2-em-3-carboxylate, prepared as described in Example 22, and ethyl mercaptan starting materials in a proportional amount to that used in this Example. The title compound was obtained as crystals in a yield of 83%. Recrystallization of this product from diisopropyl ether gave the title compound as crystals melting at 121-121.5 ° C.

/ -, ¾

121

IR spectrum (KBr), cm ^@ -1 max

1757, 1700, 1522, 1499, 1339, 1215, 1144, 839.

NMR Spectrum (CDCl3, 270 MHz) ppm:

-¾

0.07 (3H, singlet), 0.08 (3H, singlet) ·, 0.86 (9H, singlet), 1,25 (3H ·, doublet, J = 7 Hz), 1.26 (3H, doublet, J = 6 Hz), 1.34 (3H, triplet, J = 7Hz) 9 2.86 (1H, doublet of quartets, J = 12 a 7 Hz) 2.90 (1H, doublet of quartets, J = 12 a 7 Hz) 3.23 (1H, doublet of doublets, J = 3 and 6 Hz), 3 „35 (1H, doublet of quartets, J = 9 and 7 Hz), 4.20 (1H, doublet of doublets, J = 3 and 9 Hz),. 4.26 (1H, quartet, J = 6 Hz) / 5.25 (1H, doublet, J = 14 Hz), 5.46 (1H, doublet, J = 14 Hz) 9 7.66 (2H, doublet, J = 9 Hz), 8.21 (2H, doublet, J = 9 Hz). Mass spectrum (m / z): 520 (M ⁺ , C ₂ , ^H 36 ^N 2

'·· $

Example 10

4-nitrobenzyl (1R, 5S, 6S) -2 - [(3S, 5S) -5-dimethylcarbamoyl] -1- (4-nitrobenzyloxycarbonyl) -3-pyrrolidinylthio] -1-methyl-5- / 1 (R) -hydroxyethyl -1-carbapen-2-em-3-carboxylate.

122

10a) 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- [1 (R) hydroxyethyl] -1-carbapen-2-e.

The following procedure is the same as described in Example 21, but using 467 mg, 0.843 mmol of (4-nitrobenzyl (1R, 5S, 63) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6- / 1 (R)). 1-hydroxyethyl] -1-carbapen-2-em-3-carboxylate, prepared as described in Example 20, and 201 mg, 0.932 mmol of m-chloroperbenzoic acid (80% purity), 464 mg of the title compound were obtained as a crude This product was used for the next reaction without further purification.

10b) 4-nitrobenzyl (1R, 5S, 6S) -2 - [(3S, 5S) -5-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -3-pyrrolidinylthio] -1-methyl-6- / 1 (R) -hydroxyethyl-1-carbapen-2-em-3-carboxylate ml of a tetrahydrofuran solution containing 347 mg, 0.982 mmol of (2S, 4S) -dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine was cooled in an ice bath, and then 0.97 mL, 0.97 mmol of tetrahydrofuran solution containing 1M bromagnesium isopropylcyclohexylamide was added over 4 minutes to the cooled solution, then the mixture was stirred for 10 minutes. 2 ml tetrahydrofuran solution containing 464 mg of crude 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethyl-123-carbamoylphenylsulfinyl) -1-methyl-6- (1 (R) -hydroxyethyl) -1-carbapen-2-em The 3-carboxylate prepared as described in step a) above was then added to the solution and the resulting solution was stirred for an additional 30 minutes. At the end of this time, a saturated aqueous ammonium chloride solution was added, followed by water, and then the reaction mixture was extracted three times with ethyl acetate. The organic layers were separated, mixed and washed with water and then with a saturated aqueous sodium chloride solution. The solvent was removed by distillation under reduced pressure and the resulting oily residue was subjected to silica gel column chromatography (50 g). Elution with 1: 9 by volume of methanol and ethyl acetate afforded 365 mg of the title compound as a foamy solid (yield 62% based on the compound of Example 20).

IR spectrum (liquid film), in cm max

3500-3300, 1771, 1707, 1649, 1522, 1345, 1140, 855.

NMR Spectrum (CDCl3, 270 MHz) .delta. Ppm:

4 1.25 (1.5H, doublet, J = 7 Hz), 1.28 (1.5H, doublet, J = 7 Hz),  '-l 4 1.34 (3H, doublet, J = 6Hz), 1.86 - 1.99 (1H, multiplet) 2.40 - 3.20 (1H, broad), and 2.67 - 2.81 (1H, multiplet) 2.94 (1.5H, singlet), her 2.99 (3H, singlet); • j 1 3.11 (1.5H, singlet), 3.23 - 3.29 (1H, multiplet) yl 3.34 - 3.76 (3H, multiplet) < , 4 4.04 - 4.29 (3H, multiplet) 4.73 (0.5H, triplet, J = 8Hz) 'he knows 4.78 (0.5H, triplet, J = 8 Hz, • 3‘ * 5.07 (0.5H, doublet, J = 14 Hz),

ϊ

124

5.21 (1H, singlet) - - 5.22 (0.5H, doublet, J = 14 Hz), 5.23 (1H, doublet, J = 14 1 Hz), 5.43 (1H, doublet, J = 14 (Hz), 7.43 (1H, doublet, J = 3 Hz), 7.51 (1H, doublet, J = 8 Hz), 7.64 (2H, doublet, J = 8 Hz),. 8.20 (1H, doublet, J = 9 Hz), 8.17 8.22 (3H, mul tiplet).

Example 11

4-nitrobenzyl (5S, 6S) -6- [1 (R) -t-butyldimethylsilyloxyethyl] -2 - [(3S, 5S) -5-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -3-pyrrolidinylthio] -1- carbapen-2-em-3-carboxylate

The following procedure is the same as described in Example 1, but using (2S, 4S) -2-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine and crude 4-nitrobenzyl (5S, 6S) -6-. 1 (R) -tert-Butyldimethylsilyloxyethyl / -2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate, prepared as described in Preparation 4, but used without purification by column chromatography as starting materials, in a proportion similar to that of is used in this example. Title << «· ·

The 125% compound was obtained as a foam in 89% yield.

solids

IR spectrum (liquid film), ν _max cm 1779, 1709. 1657, 1522, 1345, 1136, 837.

ppm:

NMR Spectrum (CDCl3, 270 MHz), a

0.08 - 0 -, 09 (6H, multiplet) 0.87 (4.5H, singlet), 0.88 (4.5H, singlet), 1.23 ^1,27 (3H, multiplet) 1.90 - 2,03 (1H, multiplet) £ 2.65 - 2,79 (1H, multiplet) 2.93 (1.5H, singlet), 2.97 (1.5H, singlet), 4 2.99 (1.5H, singlet), 3.10 (1.5H, singlet), 3.03 - 3,30 (3H, multiplet) 3.4 9 - 3,71 (2H, multiplet) and 4.07 - 4,30 (3H, multiplet) 4.72 (1H, doublet of triplets, J = 14  'tl 5,07 (0.5H, doublet, J = 14 Hz), and 5.23 (1H, singlet) 5.25 (1H, doublet, J = 14Hz), 5.30 (0.5H, doublet, J = 14 Hz),

Δ> 44 (1H, doublet, J = 14 Hz),

7.44 (1H, doublet, J = 9Hz),

7.52 (1H, doublet, J = 9Hz),

7.65 (2H, doublet, J = 9Hz),

8.19 - 8.24 (4H, multiplet).

126

Example 12

4-Nitrobenzyl (5R, 6S) -6- [1 (R) -t-butyldimethylsilyloxyethyl] -2 - [(3S, 5S) -5-dimethylcarbampyl-1- (4-nitrobenzyloxycarbonyl) -3-pyrrolidinylthio] penem-3 -carboxylate

The following procedure is the same as described in Example 1, but using (2S, 4S) -2-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-mercaptopyrrolidine and -4-nitrobenzyl- (5R, 6R) -6-. 1 (R) -tert-Butyldimethylsilyloxyethyl / -2-ethylsulfinylpenem-3-carboxylate, prepared as described in Preparation 7, as a starting material, in a proportional amount to that used in this Example. The title compound was obtained as a foamy solid in a yield of 81%.

IR spectrum (liquid film), in _max cm ”^:

1788, 1711, 1657, 1522, 1345, 1117, 839.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 270 MHz):

0.04 (3H, singlet);

0.07 (3H, singlet);

0.83 (9H, singlet);

1.25 (3H, doublet, J = 6Hz),

1.91 - 2.05 (1H, multiplet),

2.67 - 2.85 (1H, multiplet),

127

2.93 (1.5H, singlet),

2.97 (1.5H, singlet),

2.99 (1.5H, singlet),

3.09 (1.5H, singlet),

3.46. 3.60 (1H, multiplet), 3.69 - w, 80 (2H, multiplet), 4.22 - 4.40 (2H, multiplet), 4.68 - 4.79 (1H, multiplet),

5.07 (0.5H, doublet, J = 14Hz) 5.21 (1H, doublet, J = 14  Hz), 5.23 (1H, singlet), 5.31 (0.5H, doublet, J = 14 Hz), 5.41 (1H, doublet, J 14 Hz), 5.69 (1H, singlet), 7.44 (1H, doublet, J = 9 Hz), 7.52 (1H, doublet, J = 9 Hz), 7.61 (2H, doublet, J = 9 Hz),

8.19 - 8.24 (4H, multiplet).

Example 13

4-Nitrobenzyl (5R, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -2- [2- (4-nitrobenzyloxycarbonyl) aminoethylthio] penem-3-carboxylate

128

a) The following procedure is the same as described in Example 1, but using 4-nitrobenzyl (5R, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -2-ethylsulfinylpenem-3-carboxylate, prepared as described in Preparation 7, and 2- (4-nitrobenzyloxycarbonylaminoethyl mercaptan) as starting materials, in a proportional amount to that used in this example, the title compound was obtained as a foamy solid in a yield of 76%.

b) The following procedure is the same as described in Example 4b), but using 4-nitrobenzyl (5R, 6S). butyldimethylsilyloxyethyl / -2-ethylsulfinylpenem-3-carboxylate, prepared as described in Preparation 7, and 2- (4-nitro-benzyloxycarbonyl) aminoethyl mercaptan as starting materials in a proportional amount as used in this example.

The title compound was obtained in a yield of 86%.

IR spectrum (liquid film), in cm

1788, 1725, 1607, 1522, 1347, 1119.

NMR spectrum (CDCl 3? 270 MHz), δ ppm:

0.04 (3H, singlet), 4 ', 4 0.07 (3H, singlet), .1 0.83 (9H, singlet),

H, 1.24 (3H, doublet, J = 6 Hz),

3.04 - 3.24 (2H, multiplet),

3.53 (2H, quartet, J = 6Hz),

3.73 (1H, doublet of doublets, J = 1 and 4 Hz),

4.26 (1H, doublet of quartets, J = 4 and 6 Hz), 5.18 - 5.27 (IH, multiplet), / § 5.20 (2H, singlet),

I 5.21 (IH, doublet, J = 14 Hz), those 5.42 (IH, doublet, J = 14 Hz), i-i

- 129 -

5.67 ) 1H, doublet, J = 1 Hz), 7.50 (2H, doublet, J = 9 Hz), 7.62 (2H, doublet, J = 9 Hz), 8.20 (2H, doublet, J = 9 Hz), 8.22 (2H, doublet, J = 9 Hz).

Mass spectrum (m / z): 6ol (M ⁺ (C ₃₁ H ₃₀ N ₄ O ₁₀ S ₂ Si) -terc.Bu).

Example 14

4-nitrobenzyl (5S, 6S) -6- / l (R) -trimethylsilyloxyethyl /? ² "/ ^(s) of 1- / N- (4-nitrobenzyloxycarbonyl) acetimidoyl / pyrrolidin-3-ylthio / -l-carbapen-2 -em-3-carboxylate

i) 4-nitrobenzyl (5S, 6S) -6- [1 (R) -hyaroxyethyl] -2- [2H]. .

(4-nitrobenzyloxycarbonyl Jaminoethyl thio / -l-carbapen-2-em-3-carboxylate _t was prepared in two steps from thienamycin following the procedure described í SM Schmitt et al, J. Org.

• * <*

S. Chem. (1980), 45, 1142. 140 mg, 0.239 mmol of this compound was then dissolved in 2 mL of tetrahydrofuran and 0.233 mL, 1.65 mmol of triethylamine and 0.147 mL, 1.19 mmol of trimethylsilyl chloride were added to the solution, resulting mixture was The mixture was stirred for 9 hours. Since the starting material did not dissolve, an additional 0.167 mL, 1.20 mmol of triethylamine and i

... ....

130 0.148 ml, 1.20 mmol trimethylsilyl chloride. The mixture was stirred for an additional hour. At the end of this time, the reaction mixture was dissolved with ethyl acetate and washed with ice water and then with a saturated aqueous sodium chloride solution. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (10 g). Elution with a 15:85 volume mixture of ethyl acetate and methylene chloride afforded 130 mg (83%) of the trimethylsilyl compound as crystals. Recrystallization from ethyl acetate / hexane gave crystals of the trimethylsilyl compound melting at 165-168 ° C.

IR spectrum (X 3 r), in cm ^c max

1773, 1738, 1694, 1607, 1518, 1341, 1140.

NMR Spectrum (CDCl3, 270 MHz) ppm:

0.14 (8H, singlet), 1,28 (3H, doublet, J = 6Hz) 2.91 - 3, 18 (3H, multiplet) 3.16 (1H, doublet doublets, J = 3.27 - 3, 49 (3H, multiplet) 4,11 - 4, 26 (2H, multiplet) 5.20 (2H, singlet), 5.25 (1H, ^ doublet, J = 14Hz) 5.15 - 5, 30 (1 H, multiplet) 5.48 (1H, doublet, J = 14Hz) 7.50 (2H, doublet, J = 9 Hz) 7.66 (2H, doublet, J = 9 Hz) and 8.21 (2H, doublet, J = 9 Hz) and 8.23 (2H, doublet, J = 9Hz).

(Ii) The following procedure is the same as in Example 21, but using 130 mg of the trimethylsilyl compound described in step (i) above. 137 mg of crude S-oxide were obtained.

IR-soektrum (liquid film), h, cm ^X :

max

1786, 1721, 1607, 1522, 1349, 1252, 1053.

NMR Spectrum (CDCl3, 270 MHz) [delta] ppm:

0.13 (9H, singlet);

1.25 (1.5H, doublet, J = 6Hz),

1.26 (1.5H, doublet, J = 6 Hz),

3.03 - 3.38 (4.5H, multiplet)

3.52 - 3.85 (2.5H, multiplet),

4.20 - 4.45 (2H, multiplet),

5.20 (1H, singlet).

5.22 (1H, singlet).

5.26 (0.5H, doublet, J = 14Hz),

5.30 (0.5H, doublet, J = 14 Hz),

5.43 (0.5H, doublet, J = 14 Hz),

5.47 (0.5H, doublet, J = 14 Hz),

5.62 - 5, 70 (1 H, multiplet), 7.51 (2H, doublet, J = 9 Hz), 7.62 (1H, doublet, J = 9 Hz), 7.65 (1H, doublet, J = 9 Hz), 8.22 (2H, doublet, J - 9 Hz), 8.23 (2H, doublet, J = 9 Hz).

iii) The following procedure is the same as in Example 1, but using 137 mg of the crude S-oxide obtained as described in step ii) above and 84 mg of (S) -3-mercapto-1- / N- (4-nitrobenzyloxycarbonyl) acetimidoyl / pyrrolidine. 126 mg (87% yield based on trimethylsilyl compound) of the title compound was obtained as crystals. Their recrystallization

132 from ethyl acetate-hexane gave crystals of the title compound, melting at 95-96 ° C. The physicochemical properties of this compound are similar to those described by A. Yoskida et al., Tetrahedron

Letters 25, 2793, 1984. IR spectrum (KBr) -1 , in cm ': max 1783 1700 1675, 1557, 1520, 1349, 1239, 845

NMR spectrum (CDCl3) δ ppm: 0.14 (2.25H, singlet), 0.15 (6.75H, singlet), 1.29 (3h, doublet, J = 6Hz), 1.96 - 2.17 (1H, multiplet), 2.29 (0.75H, singlet), 2.32 (2.25H, singlet), 2.30 - 2, ll (1H, multiplet), -J 3.06 - 3.31 (3H, multiplet), 3.45 - 4.07 (5H, multiplet), 4.15 - 4.27 (2H, multiplet), 5.23 (2H, singlet), 5.24 (1H, doublet, J = 14Hz), ... y 5.48 (1H, doublet, J = 14Hz), 7.56 (2H, doublet, J = 9Hz), * í 7.65 (2H, doublet, J = 9Hz), 8.20 (2H, doublet, J = 9Hz), 8.22 (2H, doublet, J = 9Hz).

Example 15 '[

4-nitrobenzyl (1R, 5S, 6S) -2 - [(3S, 5S) -5- [3- (S) - (4-nitrobenzyl) oxycarbonyl) aminopyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-3-ylthio] -6- [1 (R) -hydroxyethyl] -1-methyl-1-carbapen-2-yl-3-carboxylate

And 'i · i

- 133 ~

Using 4-nitrobenzyl (1R, 5S, 65) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- (1 (R) -hydroxyethyl) -1-carbapen-2-em-3- carboxylate, the preparation of which is described in Example 10a), and (2S, 4S) -4-mercapto-2- [3 (S) - (4-nitrobenzyloxycarbonyl) aminopyrrolidin-1-ylcarbonyl] -1-methylpyrrolidine as starting materials Compounds were prepared according to the procedure in Example 10b), as a powder in 60% yield.

_The physicochemical properties of this compound are consistent with those of the intermediate compound 45a), the synthesis of which is described in Example 45, EP No. 518 558A.

Example 15 4-Nitrobenzyl (1R, 5S, 65) -2 - [(RS) -5-oxo-3-pyrrolidinylthio] -6- [1 (R) -hydroxyethyl] -1-methyl-1-carbapen-2 -em-3-carboxylate

AND

------ 134 Following the procedure of Example 10b) using 4-nitrobenzyl- (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- (1 (R) -hydroxyethyl) 1-carbapen-2-cm-3-carboxylate, the synthesis of which is described in Example 10a) and 4-mercapto-2-oxopyrrolidine, produced the title compound as a powder in a yield of 59% by weight.

The physicochemical properties of this compound coincide with those of the intermediate whose synthesis is described in Example 11 of Japanese Patent Application Publication No. Hei 2-49783. ·

Example 17

4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6- [1 (R) -trimethylsilyloxyethyl] -1-carbapen-2-em-3-carboxylate

CONEt;

To a solution containing 8 mL of methylene chloride, 492 mL, 1.09 mmol of S-2-diethylcarbamoylphenyl 2 (R) - / (2S, 3S) -3- / 1 (R) -

- (trimethylsilyloxy) ethyl [4-oxo-2-azetidinyl] thiopropionate, the synthesis of which is described in Preparation 1, and 0.46 ml, 3.30 mmol of triethylamine and cooled in a salt-ice bath were supplied with 797 mg, 3 , 27 mmol of p-nitrobenzyloxyoxalyl chloride. The resulting mixture was allowed to react for 15 minutes at the same temperature. After addition of 0.25 mL, 3.27 mmol of isopropanol, the reaction mixture was added

135 was stirred at the same temperature for 10 minutes to quench any excess acid chloride. The reaction solution was diluted with ethyl acetate and washed twice with water and then twice with saturated aqueous sodium chloride solution. The solvent was then removed by distillation under reduced pressure. The resulting residue was suspended in toluene and the insoluble material was removed by filtration. After removal of toluene by distillation under reduced pressure, 784 mg, 4.40 mmol of dipropylethylphosphonite were added to the resulting residue, and the mixture was stirred at room temperature for 140 minutes. Excess reagent was removed by distillation under reduced pressure and the residue was dissolved in 65 ml of xylene and refluxed for 3 hours. After removal of the solvent by distillation under reduced pressure, the resulting residue was purified by column chromatography after adsorption on 50 g of silica gel. Elution with a 1: 2 by volume mixture of ethyl acetate and hexane gave the title compound containing a small amount of impurities. Subsequently, repeating the column chromatography under the same conditions afforded 535 mg of the title compound in a yield of 78% by weight. Recrystallization of this product from diisopropyl ether gave the title compound as colorless crystals, m.p.

t 202-203 ° C. ,? '-1 til IS-spextrum (KBr), in cm: max 1761, 1695, 1630, 1342, 1207.

NMR Spectrum (CDCl3, 270 MHz),% ppm:

0.10 (9H, singlet);

1.01 (3H, triplet, J = 7Hz); 0.95 - 1.20 (6H, multiplet)

1.20 (3H, doublet, J = 6Hz),

3.06 (2H, quartet, J = 7Hz),

3.05 - 3.28 (3H, multiplet)

3.45-3.80 (1H, broad singlet), ...

. «

7¾ '

136 ί * ·

4.13-4.25 (2Η, multiplet)

5.27 (1Η, doublet, J = 14 Hz),

5.47 (1Η, doublet, J = 14 Hz),

7.32 - 7.65 (4H, multiplet)

7.63 (2H, doublet, J = 9 Hz),

8.21 (2H, doublet, J = 9 Hz).

· Mass spectrum (m / z): 625 (M ^+, C ₃₁ H N _{3 O 3} C> ₇ SSi).

Example 18

4-Nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6w / 1 (R) -tert-butyldimethylsilyloxystyl] -1-carbapen-2-em-3-carboxylate

H, C

CONEt,

OTBS

I h y ϊ

According to the procedure _of Example 17, the corresponding amounts of S-2-diethylcarbamoylphenyl 2 (R) - / (2S, 3S) -3- / 1 (R) -tert-butyldimethylsilyloxyethyl / -4- oxo-2-azetidinyl / thiopropionate, the synthesis of which is described in Preparation 9 as well as in Example 1 of Japanese Patent Application Publication No. Hei 4-174099, produced the title compound in a yield of 80% by weight. Recrystallization of this product from diisopropyl ether gave the title compound as crystals, m.p. 166-166.5 ° C.

'AND

137

IR spectrum (nujol) in cm * max

1762/1693, 1633, 1340, 1210.

NMR Spectrum (CDCl3, 270 MHz) ppm:

0.06 (SH, singlet), 0.84 (9H, singlet), 1.01 (3H, triplet, J-7 Hz),

0.93 - 1.20 (5H, multiplet)

1.16 (3H, doublet, J = 6Hz),

3.00 - 3.30 (3H, multiplet)

3.07 (2H, quartet, J = 7Hz),

3.40 - 3.90 (1H, multiplet)

4.21 - 4.33 (2H, multiplet),

5.28 (1H, doublet, J = 14Hz),

5.44 (1H, doublet, J = 14Hz),

7.27 - 7.6S (4H, multiplet),

7.67 (2H, doublet, J = 9Hz),

8.21 (2H, doublet, J = 9Hz).

Mass spectrum (m / z): 667 (M ⁺ , ^C 34 ^H 45 ^N 3 ° 7 ^SS + -)

Example 19

4-nitrobenzyl (IR, 53,6S) -2- [2- (1-perhydroazepinylcarbonyl) phenylthio] -1-methyl-6- [1- (R) -tert-butyldimethylsilyloxyethyl] -1-carbapen-2-em- 3-carboxylate

’.4

COOPNB ·! *.

138 Following the procedure outlined in Example 17 and using the appropriate amounts of S-2- (1-perhydroazepinylcarbonyl) phenyl 2 (R) - / (2S, 3S) -3- [1 (R) -t-butyldimethylsilyloxyethyl] - 4-oxo-2-azetidinyl / -thiopropionate, the synthesis of which is given in Example 9 of Japanese Patent Application Publication No. WO-A-616710.

Hei 4-174099, as a starting compound, the title compound was produced in a yield of 70% by weight. Recrystallization from diisopropyl ether gave crystals of the title compound, m.p. 210-211 ° C.

IR-spectrum (KBr), in cm 0 max

1757, 1700, 1632, 1341, 1212, 1138.

NMR Spectrum (CDCl3, 270 MHz) ppm:

0.06 (6H, singlet), 0.85 (9H, singlet), 0.95 - 1 / 08 (3H, multiplet) AND 1.16 (3H , doublet, J = 6 Hz), 'and 1 1 * 40 - 1 / 85 (8H, multiplet). 3.04 - 3, 34 (5H, multiplet) 'i · 3.45 - 3i 65 (1H, broad singlet) 4.20 - 4, 36 (2H, multiplet) 5.29 (1H, doublet, J = 14 Hz), 5.46 (1H, doublet, J = 14 Hz), F 7.30 - 7, 65 (4H, multiplet) •in 7.68 (2H, doublet, J = 9 Hz), řr 8.22 (2H, doublet, J = 9 Hz). Cl Mass spectrum (m / z): 693 (M &lt; + &gt;)

(H, N, O (SSi)). 36 47 3 7 á Example 20 · '·. / ·. · .C ••' S · ´ ·.

4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -N-1-methyl-6- (1 (R) -hydroxyethyl) -1-carbapen-2-em-3-carboxylate · Λ ·

I ,, w ·

139

To a 30 mL solution of 1.072 g, 1.71 mmol of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6- (1 (R) -trimethylsilyloxyethyl) -1-carbapen -2-em-3-carboxylate, the synthesis of which is described in Example 17, in a 1: 2 mixture of methylene chloride and methanol was added 41 mg (0.195 mmol) of citric acid hydrate and stirred at room temperature for 20 minutes. After distillation under reduced pressure, the residue was purified after adsorption on 25 g of silica gel by column chromatography eluting with ethyl acetate. This gave 970 mg of the title compound as a colorless foamy solid.

IR spectrum in cm ~ max

3600-3200 (broad), 1771, 1707, 1612, 1345, 1207.

NMR Spectrum (CDCl3, 270 MHz) Jppm:

1.00 (3H, triplet, J = 7Hz),

0.94 - 1.15 (6H, multiplet)

1.30 (3H, doublet, J = 6Hz),

3.05 (2H, quartet, J = 7Hz),

3.10-3.23 (3H, mulciplet),

3.45 - 3.80 (1H, broad singlet),

4.20 (1H, quintet, J = 7Hz),

4.25 (1H, doublet of doublets, J = 2 and 9 Hz),

140 . 5.27 (1H, doublet, J = 14Hz),

5.43 (1H, doublet, J = 14 Hz), 7.31 - 7.65 (4H, multiplet),

7.67 (2H, doublet, J = 9Hz),

8.22 (2H, doublet, J = 9 Hz).

Mass spectrum (m / z): 553 (M +, C ₆ H ₇ , N ₇ C S). i £ ¹ . O 3 J. J i

Example 21

4-nitrobenzyl (IR, 5S, 6S) -2- (2-ynyl diethylkarbamoylfenylsulf) -l-methyl-o- / L (R) -trimethylsilyloxyethyl / L ^{1-carbapen-2-em-3-carboxylate}

·: · 1.

To a solution of 6 mL of methylene chloride containing 304 mg, 0.486 mmol) of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6- (1 (R) -trimethylsilyloxyethyl) -1-carbapen- 2-em-3-carboxylate, the preparation of which is described in Example 17, was supplied with 122 mg, 1.45 mmol of sodium bicarbonate. The mixture was placed in a water / ice bath and 105 mg (0.487 mmol) of m-chlorobenzoic acid (80% purity) was added to the mixture while stirring. The mixture was stirred for one hour, then diluted with methylene chloride and washed with dilute aqueous sodium bicarbonate while cooling with ice. The solvent was removed by distillation under reduced pressure.

141 g of pressure and the residue after adsorption on a 25 g silica gel column was purified by chromatography eluting with a 2: 1 by volume mixture of ethyl acetate and hexane. The title compound (260 mg, 83%) was obtained as a foamy solid.

IR spectrum (liquid film), in cm- ^X :

max

1788, 1734, 1630, 1522, 1061. NMR-: spectrum (CDCl3, 270 MHz),? ppm: 0.08 (5.4H, singlet), 0.10 (3.6H, singlet), ί 1.04 - 1,27 (12H, multiplet) t 2.98 - 3,53 (5.6H, multiplet), 3.67 (0.4H, doublet of quartets, J = = 11 and 7.Hz), 4.16 - 4,23 (1H, multiplet, 4.26 (0.6H, doublet of doublets, J = 10 and 3 Hz),  and ’? 4.34 (0.4H, doublet of doublets, J = 10 and 3 Hz), Ϊ ťí and • 4 5.35 (0.4H, doublet, .J = 14 Hz), 5.38 (0.6H, doublet, J = 14 Hz), $ 5.46 (0.4H., doublet, J = 14 Hz), -4 I? 5.50 (0.6H, doublet, J = 14 Hz), - <? p ' 7.27 - 7.36 (1H, multiplet) * t 7.50 - 7.73 (4H, multiplet) J 7.84 - 7,90 (0.4H, multiplet), 8.15 - 8.26 (2.6H, multiplet).

Mass spectrum (m / z): 641 (M ^& lt ^{; +} &gt;, C18H18N3O5Si).

·, Ί in Ϊs Λ. 41 'ί # 4

142

Example 22

4-Nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbanoylphenylsulfinyl) -1-methyl-5- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-carbapsn-2-em-3-carboxylate

Following the procedure of Example 21 and using 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6- [1- (R) -tert-butyldimethylsilyloxyetnyl] -1-carbapen-2 -em-3-carboxylate, prepared as described in Example 18 - corresponding amount ^of the starting compounds was prepared the title compound in a yield of 87% by weight of a foamy solid.

IR (Nujol) ^{cm max}

1788, 1735, 1630, 1523, 1058.

NMR Spectrum (CDCl3, 270 MHz), .delta. Ppm:

0.03 - 0.06 (6H, multiplet)

0.83 (4.5H, singlet),

0.84 (4.5H, singlet),

1.05 - 1.27 (12H, multiplet)

2.98 - 3.56 (5.5H, multiplet),

143 -

3.59 (0.5H, doublet quaternary, J = 10 and 7 Hz), 4.20 - 4,38 (1H, multiplet) 4.30 (0.5H, doublet of doublets, J = 11 and 3 Hz),. 4.39 (0.5H, doublet of doublets, J = 11 and 3 Hz), 5.34 (0.5H, doublet, J = 14 Hz), 1 5.38 (0.5H, doublet, J = 14 Hz), 5.45 (0.5H, doublet, J = 14 Hz), 5.49 (0.H, 5H, doublet, J = 14Hz), 7.29 - 7.36 (1H, multiplet) 7.50 - 7,71 (4H, multiplet) 7.85 - 7,89 (0.5H, multiplet), 8.15 - 8.25 (2.5H, multiplet). Mass spectrum (m / z): 633 (M ^& lt ^{; +} &^gt; ^H 45 ^N 3 ° 8 ^SSI) ·

Example 23 '

4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenyl) sulfinyl) -1-methyl-6- [1 (R) -hydroxyethyl] -1-carbapen-1-yl -3-carboxylate

- '' va '%

To 10 ml methylene chloride solution containing 554 mg, N 1.00 mmol of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoyl-phenylthio) -1-methyl-6- (1 (R) -hydroxyethyl) -1-carbapen-2-yl-3-carboxylate, the synthesis of which is described in Example 20;

144 ice-cooled was first supplied with 1.5 ml, 1.5 mmol of aqueous sodium bicarbonate solution and then 215 mg, 1.00 mmol of m-chloroperbenzoic acid (80% purity). The resulting reaction mixture was stirred at the same temperature for 90 minutes. After the aqueous sodium sulfite solution was added to the reaction solution, the reaction mixture was stirred for 10 minutes. The reaction solution was diluted with methylene chloride, cooled with ice, washed with aqueous sodium bicarbonate solution and evaporated under reduced pressure. The resulting residue was purified after adsorption on 50 g of silica gel, purified by column chromatography eluting with ethyl acetate. 145 mg (25% yield) of the resulting low polarity compound (isomer is due to the S-oxide configuration) followed by 96 mg (17% yield) of the resulting high polarity compound isomer, both isomers as a foamy solid.

Lower polarity S-oxide:

IR spectrum (liquid film), ⁱⁿ max cm:

3500-3300, 1786, 1732, 1624, 1522, 1200, 1061.

NMR Spectrum (CDCl3, 270 MHz) & ppm:

1,02

1/24

3.01

3.12

3.18

3.32 3,39

4.19 4.28 5.38 5.52

7.33

- 1.11 (6H, multiplet), (6H, triplet, J = 7Hz), (1H, doublet of quartets, J = 10 and 7Hz), (2H, quartet, J = 7Hz),

- 3,30 (1H, multiplet), (1H, doublet of doublets, J = 3 and 6 Hz),

- 3.52 (1H, multiplet),

(1H, quintet, J = 6Hz), (1H, doublet of doublets, J = 3 a 10 Hz), (1H, doublet, J = 14 Hz), (1H, doublet, J = 14 Hz), (1H, doublet of doublets, J = 1 a 8 Hz),

IN?

145

7.58 (1H, doublet of triplets, J 7.66 (1H, doublet of triplets, J 7.70 (2H, doublet, J = 9 Hz)), 8> 1δ (1H, doublet of doublets, J ^; 8.24 (2H) , doublet, J = 9 Hz).

and 8 Hz), 1 and 8 Hz), and 8 Hz),

S-oxide with higher polarity:

IR spectrum (liquid film), in cm ^-1 :

^{c J} max

3500-3300, 1736, 1734, 1624, 1522, 1198; 1061.

NMR Spectrum (CDCl270 MHz), -Tppm:

0.83 (3H, doublet, J = 7 Hz), 1.09 (3H, triplet, J = 7Hz), 1.18 (3H, triplet, J = 7Hz), 1,23 (3H, doublet, J = 6 Hz), 3.18 (2H, quartet, J = 7Hz), 3.20 - 3, 35 (1K, multiplet) 3.40 - 3, 53 (1 H, multiplet), 3.47 (1H, doublet of doublets, J = 3 a 6 Hz), 3.70 (1H, doublet of quartets, J = 10 and 7 Hz) 4.25 (1H, quintet, 6 Hz), 4.38 (1H, doublet of doublets, J = 3 a 10 Hz), 5.34 (1H, doublet, J = 13 Hz), 5.48 (1H, doublet, J = 13 Hz),

ie

, · Ί /

/ -1

7.28 - 7.32 (1H, multiplet), 7.48 - 7.56 (2H, multiplet), 7.65 (2H, doublet, J = 9 Hz), 7.85 - 7.91 (1H, multiplet)

8.22 (2H, doublet, J = 9 Hz).

Mass spectrum (m / z): 551 (M ^{+ (C} 28 ^H 31 ^N 5 ^S ^ ° 8 ° 2 ° ^H

- 146 Example 24

4-nitrobenzyl (1R, 5S, 6S) -2- [2- (lperhydroazepinylcarbonyl) -phenylsulfinyl] -1-methyl-6- / 1 (R) -tert-butyldimethylsilyloxyethyl] -1-carbapen-2-3m-3- carboxylate

According to the procedure described in Example 21 and using an appropriate amount of 4-nitrobenzyl (1R, 5S, 6S) -2- [2- (1-perhydroazepinylcarbonyl) phenylthio] -1-methyl-6- / 1 (R) -tert-butyldimethylsilyloxyethyl 1-carbapen-2-em-3-carboxylate, the synthesis of which is described in Example 19, as starting compound i.

the title compound was produced in a yield of 89% by weight as a foamy solid.

IR spectrum (liquid film) in cm

1790, 1734, 1628, 1524, 1347, 1061.

NMR Spectrum (CDCl3, 270 MHz) .delta. Ppm:

0.03, 0.04, 0.05, 0.06 (together 6H, each singlet), 0.75 (1.5H, doublet, J = 7 Hz),

0.83 (4.5H, singlet),

0.84 (4.5H, singlet),

1.13 (1.5H, doublet, J = 6 Hz),

147

1.16 (1.5H, doublet, J = 6 Hz),

1.23 (1.5H, doublet, J = 7 Hz),

1.44 - 1.80 (8H, multiplet)

3.00 (0.5H, doublet of quartets, J = 10 and 7 Hz), 3.11 - 3.37 (3.5H, multiplet),

3.41 - 3.50 (1H, multiplet),

3.60 - 3.77 (1H, multiplet),

4.19 - 4.31 (1.5H, multiplet)

4.33 (0.5H, doublet doublet, J = 10 and 3 Hz), 5.33 (0.5H, doublet, J = 14Hz) 5.40 (0.5H, doublet, J = 14Hz) 5.46 (0.5H, doublet, J = 14Hz) ? · 5.49 (0.5H, doublet, J = 14Hz) 7.27 - 7.32 (0.5H, multiplet) 7.36 (0.5H, doublet doublets, J = 7 and 1 Hz), 7.48 - 7,60 (1.5H, multiplet) 7.63 - 7.73 (2.5H, multiplet) 7.93 - 7.96 (0.5H, multiplet) ΐ 8.15 (0.5H, doublet doublets, J = 8 and 1 Hz),

j 8.22 (1H, doublet, J = 9 Hz), > 8.23 (1H, doublet, J = 9 Hz).

⁴ Mass spectrum (m / z): 709 (M ⁺ , ^C 36 ^H 47 ^N 3 ° 3 ^SSi ')

Example 25

AND

4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenyl) sulfonyl) -1-methyl-6- [1 (R) -ter. butyldimethylsilyloxyethyl] -1-carbapen-2-em-3-carboxylate

148

1794 1748 1636 1524 1320

NMR Spectrum (CDCl3, 270 MHz)

To 3 mL of a methylene chloride solution containing 157 mg, 0.235 mmol of 4-nitrobenzyl (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-carbapen -2-em-3-carboxylate, the synthesis of which is described in Example 18, ice-cooled, was first supplied with 78 mg,

0.93 mmol sodium bicarbonate followed by 78 mg,

0.52 mmol of m-chloroperbenzoic acid (80% purity). The reaction mixture was stirred at constant temperature for 20 minutes. Aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred for 10 minutes. The reaction solution was diluted with methylene chloride, washed with aqueous sodium bicarbonate solution and evaporated under reduced pressure. The resulting residue was purified by column chromatography after adsorption onto 15 g of silica gel. Elution with ethyl acetate: hexane (4: 6 by volume) gave the title compound (148 mg, 90% yield) as a foamy solid.

IR spectrum (liquid film) in cm -1:

max

1266, 1161.

$ ppm:

% and 0.03 0.05 (3H, (3H, 0.83 (9H, 1.06 (3H, AND 1.16 (3H,

singlet), singlet), singlet), triplet, J = 57 Hz, doublet, J = 6 Hz),

149

1.20 - 1.43 (5H, multiplat), 3.01 - 3.19 (2H, multiplat), 3.24 - 3.34 (4H, multiplet) 4.19 - 4.23 (1H, multiplet) 4.42 - 4.52 (1H, multiplet) IN 5.39 (2H, singlet 7.25 -7.34 (1 H, multiplet) * 7.43 - / ..65 (2H, multiplet) 7.52 (2H, doublet, J = 9Hz) 3.11 (1H, doublet, J = 3 Hz) 3.21 (2H, doublet, J = 9Hz). Mass spectrum (m / z): 700 (M ⁺ (C ₃₄ H ₄₅ N ₃ O _with SS.i) + 1).

Preparation 1 of S-2-diethylcarbamoylphenyl 2 (R) - / (2S, 3S) -3- / 1 (R) - (trimethylsilyloxy) ethyl] -4-cis-2-azetidinyl / thiopropionate

1 'i

h ₃ c

To 20 ml of tetrahydrofuran solution containing 1.002 g, 2.03 mmol of S-2-diethylcarbamoylphenyl 2 (R) - / (2S, 3S) -3- / 1 (R) -tert-butyldimethylsilyloxyethyl] -4-oxo-2-azitidines1 thiopropionate, the synthesis of which is described in Preparation 9 as well as in Example 1, in particular in Japanese Patent Application No. Hei

• 3

150 ii, · f

_v s'

§ '..

4-174009, and the mixture was heated to 50 ° C for 3 hours.

After cooling the solution and extracting with ethyl acetate, the organic extract was washed with a saturated aqueous solution of sodium bicarbonate, water, and then with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 10 mL of tetrahydrofuran, followed by 0.60 mL, 4.3 mmol of tetraethylamine and 0.53 mL of trimethylsilyl chloride was added to the resulting solution. The reaction mixture was stirred at room temperature for 80 minutes and then at 40 ° C for 100 minutes. After cooling the reaction mixture and diluting with ethyl acetate, the mixture was washed twice with ice-water and then once with saturated aqueous sodium chloride. The solvent was removed by distillation under reduced pressure. The resulting solution was adsorbed onto a 50 g silica gel column and purified by column chromatography eluting with ethyl acetate: hexane (3: 2 to 4: 1) to give the title compound (742 mg, 81%) as a foamy solid.

IR spectrum, (liquid film), h. cm ΓΠ3Χ

3250, 1760, 1700, 1625.

NMR Spectrum (CDCl3, 270 MHz), .delta. Ppm:

0.12 (9H, singlet);

1.03 (3H, triplet, J = 7Hz),

1.23 (3H, doublet, J = 6Hz),

1.25 (3H, triplet, J = 7Hz),

1.22 - 1.31 (3H, multiplet) 2.95 - 3.12 (4H, multiplet), 3.25 - 3.85 (2H, multiplet), 3.90 (1H, doublet of doublets, J = 2 and 4 Hz), 4.14 (1H, quintet, J = 6Hz), 6.07 - 6.18 (1H, broad singlet),

151 7.32 - 7.35 (1H, multiplet), 7.41 - 7.51 (3H, multiplet).

Mass spectrum (m / z)

450 (M ⁺ ,

Preparation 2

4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2-phenylsulfinyl-1-arbapen-2-em-3-carboxylate

'-. Following the procedure of Example 21 and using

Tg of 4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2-phenylthio-1-carbapen-2-em-3-carboxylate, the preparation of which is described in of Example 7, in an appropriate amount as the starting compound used in said compound

Example, a compound was produced which was purified after adsorption onto a silica gel column by chromatography. Elution with a mixture of diethyl ether and methylene chloride with a volume ratio gradient of 5: 95 to 20:80 gave low-polarity S-oxide crystals with a yield of 62% by weight and high-polarity foamed STj-oxide with a yield of 30% by weight. Recrystallization of the low-polarity S-oxide from ethyl acetate / hexane gave crystals of this isomer, m.p. 150-151 ° C.

152

Low Polarity Isomer:

IR spectrum (KBr), cm @ -1: ^c max

1796, 1715, 1528, 1335, 1044, 839.

Δ NMR (CDCl 3, 270 MHz) δ ppm:

0.06 (3H, singlet), 0.07 (3H-, singlet), 0.73 (3H, doublet, J = 7 Hz), 0.85 (SH, singlet), 1.18 (3H, doublet, J = 6 Hz), 3.27 (IH, doublet of doublets, J = 3 and 5 Hz), 3.90 (1H, doublet of quartets, J = 11 and 7 Hz) 4.23 (1H, doublet of quartets, J = 5 and 6 Hz), 4.41 (1H, doublet of doublets, J = 3 and 11 Hz), 5.36 (1H-, doublet, J = 14 Hz), 5,56 (1H, doublet, J = 14 Hz),

7.46-7.53 (3H, multiplet),

7.66 (2H, doublet, J = 9Hz),

7.72-7.78 (2H, multiplet)

8.24 (2H, doublet, J = 9 Hz).

j High polarity isomer:

$ H 'IR (kaoalný film) in cm s ^x - ¹ max "in 1783, 1730, 1524, 1319, 1273, 1047, 837th

NMR Spectrum (CDCl3, 270 MHz) (/ ppm:

/ ' 0.04 0.05 (3H (3H 0.83 (9H 1.15 (3H 1.39 (3H 3.16 (1H

singlet), singlet), singlet), doublet, J = 6 Hz), doublet, J - 7 Hz), doublet of quartets, J = 10 and

153

3.39 4.16 4.26

5.40 5.49 7.51 7.68 (1H, doublet of doublets, J = 3 and 4 Hz), (1H, doublet of doublets, J = 3 and 10 Hz), (1H, doublet of quartets, J = 4 and 6 Hz) ), (13, doublet, J = 14Hz), (1H, doublet, J = 14Hz),

- 7.58 (3H, multiplet), (2H, doublet, J = 9 Hz),

7.68-7.73 (2H, multiplet), 8.23 (2H, doublet, J = 9 Hz).

Mass spectrum (m / z) (both isomers)

534 (M ⁺ _{2 g} H ₃ C _& N ₂ O ₇ SSi).

Preparation 3

4-Nitrobenzyl (IR, 53,6S) -5- [1 (R) -tert-butyldimethyl-3-yloxy] ethyl-1-methyl-2-phenylsulfonyl-1-carbane-2-em-3-carboxylate

The compound was prepared according to the procedure outlined in i

Example 21 using the 4-nitrobenzyl (IR, 5S, 6S) -6- (1 (R) -tert-butyldimethylsilyloxyethyl) -1'-methyl-2-phenylsulphins 11-carbapen-2-em-3 isomer of high polarity The synthesis is described in Preparation 2, in an appropriate amount as the starting compound. The title compound * was obtained in 87% yield as a foamy solid.

154

IR spectra (liquid film), in cm ^-1 :

1796, 1750, 1524, 1316, 1264, 1161, 1079, 837.

NMR- spect rum (CDCl ₃ , 270 MHz) J ppm: 0.03 <3H, singlet), 0.05 (3H, singlet),. 0.84 (9K, singlet), 1.16 (3K-, doublet, J = 6 Hz), 1.19 (3H, doublet, J = 7 Hz), 3.40 (1H, doublet of quartets, J = 11 a 7 Hz), 3.46 - 3, 52 (1 H, multiplet), 4.23 (1H, doublet of quartets, J = 4 and 6 Hz), 4.44 (1H, doublet of doublets, J = 4 and 11 Hz), 5.45 (2H, singlet), *

7.51 - 7.53 (2H, multiplet),

7.60 - 7.68 (3H, multiplet)

8.00 (2H, doublet, J = 9Hz),

3.23 (2H, doublet, J = 9 Hz).

Mass spectrum (m / z): 543 (M ^+, (C ~ _N H_, .N_O ,, SSi) -t-2u) ·.

z y j o z o

Preparation4 i

4-nitro-benzyl (5S, SS) -5- [1 (R) -tert-butyldimethylsilyloxyethyl] -4-phenylsulfinyl-1-carbapen-2-em-3-carboxylate

- 155

Following the procedure of Example 21 and using 4-nitrobenzyl (5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -3-phenylthio-1-carbapen-2-em-3-carboxylate (Tetrahedron Letters 25 , 2793 (1984)) as the starting compound in an appropriate amount. The resulting product was separated and purified after column chromatography on silica gel, eluting with ethyl acetate / hexane (4: 6, v / v). This gave a low-polarity S-oxide in the form of crystals with a yield of 43% by weight and a high-polarity S-oxide in the form of a pan-shaped solid. Recrystallization of the low-polarity S-oxide to diisopropyl ether gave crystals having a melting point of 111.5-114 ° C.

Low Polarity Isomer:

IR (XBR), ^r max cm

1786, 1723, 1507, 1526, 1323, 1206, 1044, 837.

NMR Spectrum (CDCl3, 270 MHz) & ppm:

.ii

'and 0.05 (3H, singlet), • φ 0.06 (3H, singlet) ·, 0.85 (9H, singlet), ? Mrs. 1.17 (3H, doublet, J = 6 Hz),  fe 2.55 (1H, doublet of doublets, J = 9 and 18 Hz), 3.08 (1H, doublet of doublets, J = 3 and 5 Hz), 3.51 (1H, doublet of doublets, J = 11 and 18 Hz) 4.18 (1H, doublet of quartets, J = 5 and 6 Hz), 4.37 (1H, double doublet of doublets, J = 3, 5.37 (1H, doublet, J = 14 Hz), / 'J 5.54 (1H, doublet, J = 14 Hz), . . 7.48 - 7, 54 (3H, multiplet) p 7.65 (2H, doublet, J = 9 Hz), <í 7.70 - 7, 77 (2H, multiplet) and 8.24 (2H, doublet, J = 9 Hz).

iJ ’

Mass spectrum (m / z): 5'70 (M ⁺ , C ₂ H ₃₄ N ₂ O ₇ SSi).

156

High polarity isomer:

IR-soektrum (caaal film), in cm - · max

1790, 1723, 1607, 1524, 1322, 1269, 1044, 837.

NMR Spectrum (CDCl3, 270 MHz) porn:

0.05 (3H, singlet), 0.06 (3H &gt;) singlet), 0.84 (9K, singlet), - 1.18 (3H, doublet, J = 6 Hz), 2.80 (1H, doublet of doublets, J = 11 and 19 Hz), 3.29 (1H, doublet of doublets, J = 8 and 19 Hz), 3.34 (1H, triplet, J = 3Hz) 4.17 - 4, 30 (2H, multiplet) 5.40 (1H, doublet, J = 14 Hz), 5.49 (1H, doublet, J = 14 Hz), 7.49 - 7, 55 (3H, multiplet) 7.63 (2H, doublet, J = 9 Hz), 7.70 - 7, 76 (2H, multiplet); 8.23 (2H, doublet, J = 9 Hz).

Preparation 5

4-Nitrobenzyl (1R, 53,6S) -6- [1 (R) -tert-butyldimethylsilyl oxyethyl] -1-methyl-2- / 2- (4-nitrobenzyloxycarbonyl) aminoethylsulfinyl] -1-carbapen-2- em-3-carboxylate

OTBS and CH ₃ O

I H i, ΝΗ — PNZ

H ₃ C '

-NCOOPNB

157

Following the procedure of Example 21 and using appropriate amounts of 4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -1-methyl-2- / 2- (4-nitrobenzyloxycarbonyl) The aminoethylthio] -1-carbapen-2-em-3-carboxylate, the preparation of which is described in Example 5, produced a foamed solid of the title compound in a yield of 92% by weight.

IR (liquid film), ^max

1786, 1721, 1607, 1522, 1347, 1254, 1048.

NMR Spectrum (CDCl3, 270 MHz) .delta. Ppm:

0.07 (3H singlet) 0.09 (3H singlet) 0.86 (9H singlet) 1,23 (1.5H, doublet, J = 6Hz), - 1.24 (1.5H, doublet, J = 6Hz), 1.39 (1.5H, doublet, J = 7Hz), 1.40 (1.5H, doublet, J = 7Hz), 3.12 - 3.45 (3H, multiplet), 3.60 - 3.92 (3H, multiplet), 4.29 (1H, quartet, J = 6Hz), 4.34 (0.5H, doublet of doublets, J = 3 and 10 Hz), 4.46 (0.5H, doublet of doublets, J = 3 and 10 Hz),

5.14 - 5.46 (2H, multiplet)

5m23 (2H, singlet)

5.68 - 5.77 (1H, multiplet),

7.51 (1H, doublet, J = 9Hz),

7.52 (1H, doublet, J = 9Hz),

7.61 (1H, doublet, J = 9Hz),

7.66 (1H, doublet, J = 9Hz),

8.20 - 8.24 (4H, multiplet).

Mass spectrum (m / z): 705 (M ⁺ , (C, HH (N CO jO SSSiJ -CH ^).

153

Preparation 6

4-nitrobenzyl (1R, 5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxy] ethyl-1-methyl-2-3-thylsulphins 11-ethyl-1-carbapen <% · -2-em-3-carboxylate

Using an appropriate amount of 4-nitrobenzyl (1R, 5S, 65) -6- [1 (R) -t-butyldimethylsilyloxyethyl] -2-.

Ethylthio-1-methyl-1-carbapen-2-em-3-carboxylate, the preparation of which is given in Example 9, as the starting compound and following the procedure of Example 21, the synthesis of the title compound was carried out. The title compound was a foam-like solid. Yield 92%.

Infrared Absorption Spectrum (liquid film) in cm / - ^J max '1784, 1715, 1524, 1333, 1055, 837th

; NMR Spectrum (CDCl3, 270 MHz), ppms »

0.08 (3.6H, singlet),

0.09 (2.4H, singlet) * 0.86 (9H, singlet) / 1.24 (3H, doublet, J = 6 Hz);

j 1.39 (3H, doublet, J = 7Hz),

1.41 (1.8H, triplet, J = 7Hz), * 1.44 (1.2H, triplet, J = 7Hz),

159 B »mW« 88aBsa6 «ga? G» gžt ^ <Í ··

2.93 - 3,10 (2H, multiplet) 3.38 (0.6H, doublet doublets, J = 3 and 5 Hz), 3.41 (0.4H, doublet doublets, J = 3 and 5 Hz), 3.61 (0.6H, doublet quartets, J = 10 and 7 Hz) 3.85 (0.4K, doublet quartets, J = 10 and 7 Hz) 4.23 - 4,34 (1.6H, multiplet) 4.42 (0.4H, doublet doublets, J = 3 and 10 1 Hz), 5.27 (0, 4H, doublet, J = 14Hz) 5.23 (0.6H, doublet, J = 14Hz) 5.41 (0.6H, doublet, J = 14Hz) 5.44 (0.4H, doublet, J = 14Hz) 7.63 (1.2H, doublet, J = 9 Hz) 7.66 (0.8H, doublet, J = 9 Hz) 8.23 (2H, doublet, J = 9 Hz).

Mass spectrum (m / z): 479 (M ⁺ , (C-C 11 H 15 N 2 O-SSi) -c-3u).

'25 ob 2 7

Preparation 7

4-Nitrobenzyl (5S, 6S) -6- [1 (R) -tert-butyldimethylsilyloxy ethyl] -2-ethylsulphinyllpenem-3-carboxylate

160 ml methylene chloride solution containing 1,039 g,

1.98 mmol of 4-nitrobenzyl (5R, 6S) -6- [1 (R) -tert-butyldimethylsilyloxyethyl] -2-ethylthiopenem-3-carboxylate was cooled in an ice bath and then carefully added to the cooled solution over 5 minutes mg of m-chloroperbenzoic acid (purity 80%). The reaction mixture was stirred at the same temperature for 30 minutes. After the addition of 88 mg of m-chloroperbenzoic acid (purity &lt; - &gt; 8O &apos;

The reaction mixture was diluted with methylene chloride and washed with dilute aqueous sodium carbonate solution. The organic portion was evaporated under reduced pressure and the resulting residue adsorbed onto a 50 g silica gel column was purified by chromatography. Elution with ethyl acetate / hexane (4: 6) yielded:

202 mg (w. 19% yield) of low-polarity S-oxide as a foamy solid, as ^follows:

336 mg (31% yield) of a 1: 3 mixture of low-polarity S-oxide and high-polarity S-oxide / 72 mg of high-polarity S-oxide (7% yield).

All three fractions which were obtained separately by column chromatography were combined again to give the starting compound used in Examples 12 and 13.

**. Low Polarity Isomer:

'ř

IR spectrum (liquid film), in cm ^X :

ΓΠαΧ r. 1796, 1701, 1524, 1323, 1063.

^of d '/ NMR (CDCl @, 270MHz) CTPP:

; 0.05 (3H, singlet),

4 * 0.08 (3H, singlet);

161

0.84 (9H singlet) 1.26 (3H, doublet, J = 6Hz), 1.44 (3H, triplet, J = 7Hz) - X 3.10 (2H, quartet, J = 7Hz), 3.92 (1H, doublet of doublets, J = 1 and 3 Hz), 4.28 (1H, doublet of quartets, J = 3 a 6 Hz), 5.26 (1H, doublet, J = 14Hz), 5.38 (1H, doublet, J = 14Hz), 5.73 (1H, doublet, J = 1Hz), 7.62 (2H, doublet, J = 9Hz), 8.23 (2H, doublet, J = 9Hz). · ₄ High polarity isonter: IR spectrum (liquid film), in max cm * - · * 1794, 1702, 1524, 1321, 1063. · ’' NMR Spectrum (CDCl3, 270 MHz) c> ppm : ⁴ · 0.04 (3H singlet) 0.07 (3H singlet) 0.82 (9H singlet) 1,25 (3H, doublet, J = 6Hz), ^x '1 1.44 (3H, triplet, J = 7Hz) 3.13 (2H, doublet of quartets, J = 4 a 8 Hz), 3.90 (1H, doublet of doublets, J = 2 and 4 Hz), 4.27 (1H, doublet of quartets, J = 4 a 6 Hz), .? ' Λ ’ 5.22 (1E, doublet, J = 14Hz), 5.41 (1H, doublet, J = 14Hz), 1 5.85 (1H, doublet, J = 2Hz), 7.59 (2Ή, doublet, J = 9 Hz), • '· φ and 8.23 (2H, doublet, J = 9Hz).

, .ι

- 162 Preparation 8

4-nitrobenzyl (1R, 5S, 6S) -2 - [(3S, 5S) -5-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -3-pyrrolidinylthio] -1-methyl-6- / 1 (R) -hydroxyethyl 1-carbapen-2-em-3-carboxylate

To 2 ml of a solution containing 55 mg of 4-nitrobenzyl (1R, 5S, 6S) -2 - [(3S, 5S) -5-dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -3-pyrrolidinylthio] -1-methyl-6- The (1) (R) -trimethylsilyloxyethyl] -1-carbapen-2-em-3-carboxylate, prepared as described in Example 1, was treated with 8 mg (0.039 mmol) of citric acid hydrate and stirred at room temperature. 35 minutes. The solvent was then removed by distillation under reduced pressure, and the residue was purified by adsorption on 5 g of silica gel by column chromatography eluting with methanol: ethyl acetate (1: 9) to give the title compound (42 mg, 84%) as a glassy solid.

The physicochemical properties of this compound are consistent with those of the compound prepared in Example 10.

'tji

- 163 Preparation 9

S-2-Diethylcarbamoylphenyl 2 (R) - ((2S, 3S) -3- / 1 (R) - (tert-butyldimethylsilyloxy) ethyl) -4-oxo-2-azetidinyl / thioorooionate

9a) 1-tert-Butyldimethylsilyloxy-1- (2-diethylcarbamoyl) phenylthio-1-propene

To a solution of 3.20 g, 12.1 mmol of S- (2-diethylcarbamoyl) phenylthiopropionate, the synthesis of which is described in Reference Example 12, published Japanese Patent Kokai Application No. Hei 4-174 099, and 3.64 g, 24, 1 mmol of tert-butyldimethylsilyl chloride in a mixture of 12 ml of dimethylformamide and 12 ml of tetrahydrofuran was added 1.7 ml, 12.2 mmol of triethylamine. The resulting reaction mixture was stirred at room temperature for 3 minutes and then the solution was cooled to -73 ° C. 12.1 ml of a 1.0 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran was added dropwise to the reaction mixture over 20 minutes. The reaction mixture was stirred at constant temperature for 30 minutes.

F

After addition of 10 ml of saturated aqueous sodium bicarbonate solution, the reaction mixture was extracted with hexane and the extract was washed twice with water, once with 2N aqueous sodium hydroxide solution, three times with water and once with saturated aqueous sodium chloride solution. The extract was dried over anhydrous sulfate

The magnesium phase and the solvent were removed by distillation under reduced pressure. The residue was dissolved in hexane and the resulting solution was mixed with 9.0 g of alumina for chromatography and stirred for 15 minutes. The aluminum oxide was removed from the mixture by filtration and washing with hexane. The filtrate and washings were combined. After removal of the solvent by distillation under reduced pressure, 4.24 g of Z (O) -1-tert-butyldimethylsilyloxy-1- (2-diethylcarbamoyl) phenylthio-1-propene was obtained. NMR spectroscopy (270 MHz) analysis showed a ratio of Z (O) -isomer to E (O) -isoraer in the compound greater than 20.

9b) S-2-Diethylcarbamoylphenyl 2 (R) - [(2S, 3S) -3- / 1 (R) - (tert-butyldimethylsilyloxy) ethyl] -4-oxo-2-azetidinyl] thiopropionate

To a solution of 4.24 g of Z (O) -1-tert-butyldimethylsilyloxy-1- (2-diethylcarbamoyl) phenylthio-1-propene, the synthesis of which is described in previous Preparation 9a) and 1.57 g, 5.47 mmol ( 3R, 4S) -3- [1 (R) -tert-Butyldimethylsilyloxyethyl] -4-acetoxy-2-azetidinone in 55 ml methylene chloride, 1.4 g 10.9 mmol colorless zinc chloride was added. The reaction mixture was heated under reflux for 40 minutes and then cooled to room temperature. After removal of the solvent by distillation under reduced pressure, the residue was dissolved in ethyl acetate. The solution was washed three times with water and once with saturated aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was recrystallized from about 10 ml of diisopropyl ether. This gave 2.08 g of crystals (77% yield), m.p. 130.5-132 ° C.

, .ι

- Ρ * *

Μ

.1.-Λ

U 'U> ί

165

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 270 MHz) δ ppm: 0.03 (6H, singlet), 0.87 (9H, singlet), 1.03 (4H, triplet, J = 7Hz), 1,21 (3H, doublet, J = 6 Hz), 1,25 (3H, triplet, J = 7Hz), 1.29 (3H, doublet, J = 7 Hz),  with* 2.96 - 3, 15 (4H, multiplet) 3.20 - 3, 85 (2H, broad), 3.96 (1H, dd, J = 2.4 Hz), 4.19 (1H, quartet, J = 6 Hz), 5.90 - 5, 10 (1H, broad singlet) 7.30 - 7, 35 (1 H, multiplet) 7.41 - 7, 51 (3H, multiplet). Mass spectrum (m / z): 492 (M ⁺ , ^c 25 ^H 40 ^N 2 ^O 4 ^{SSi) e}

Represented by:

Claims (44)

PATENT CLAIMS A process for the preparation of carbapenem compounds and compounds of the formula (I) wherein: · R ³ represents hydrogen or a carboxyl protecting group, 2 3. R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, and groups of the formula CH. -C - R ' OR ⁶ where R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or a hydroxy protecting group, or ^R @ 3 and R @ 2 together represent a group of the formula = C (CH3) CH --OR @ 3 in which R @ 3 is as defined above; 167 X represents a sulfur atom or a group of the formula> CHR ⁷ , wherein R ⁷ represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbon atoms, and A represents an alkyl group having from 1 to 5 carbon atoms and which is unsubstituted or substituted by 1 or 2 'substituents selected from the group consisting of substituents A as defined below, an aryl group as defined below, an aralkyl group in which an alkyl group having from 1 to 6 carbon atoms is substituted at least once by said aryl group, a heterocyclic group having from 3 to 10 ring atoms, at least one of said atoms being a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, said group being unsubstituted or substituted by at least one substituent selected from a group consisting of B on carbon, B ^3, on nitrogen heteroatoms and oxygen atoms to form a sulfinyl or sulfonyl group on sulfur heteroatoms, all as defined below, fused heterocyclic groups in which the heterocyclic group is as defined above is fused to an aryl group as defined below; or. an alkyl group having from 1 to 6 carbon atoms; -168 which is substituted with at least one substituent selected from the group consisting of heterocyclic groups and fused heterocyclic groups as above, said aryl groups are aromatic carbocyclic groups having from 6 to 14 carbon ring atoms and are unsubstituted or substituted with at least one substituent selected from the group consisting of defined below. substituents C, - · said substituents A are selected from the group consisting of hydroxy, protected hydroxy, nitro, amino, protected arnihc groups, groups of formula Η ^^ ΝΒ ¹⁰⁾ ^ ¹¹ !! ¹² , where R ¹ ®, ^R11 and ^R12 are independently selected from the group consisting of hydrogen atoms, amino protecting groups and alkyl groups having from 1 11 12 to 6 carbon atoms, or R and R together represent a group of formula - (CH₂) m - wherein n is an integer from 2 to ^{10, and} II, 6, or R and R together represent a group of the formula ~ (CH ") -, wherein p is 2 or 3 AZP ^J groups of formula -NR ¹³ C (= NR ¹⁴⁾ R ¹³ where 13 14. , R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, and alkyl groups having from 1 to 6 carbon atoms, and R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an amino group or a protected amino group, or * - 169 any two of R ^3-3 , r ^ ⁴ _and ^ 15 together represent a group of formula - (CH-) - wherein p is 2 or 3, Wherein said B substituents are selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, hydroxy groups, halogen atoms, cyano groups, nitro groups, alkoxycarbonyl groups having from 2 to 7 carbon atoms, carboxy groups, oxygen atoms to form a carbonyl group with a ring carbon atom, cycloalkyl groups having from 3 to 7 ring carbon atoms, alkoxyalkyl groups in which the alkoxy and alkyl moieties have from 1 to 6 carbon atoms, alkoxycarbonylalkyl groups in which the alkoxy and alkyl moieties having from 1 to 6 carbon atoms, 170 cyanoalkyl groups in which the alkyl moiety has from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkanoyloxy groups having from 1 to 6 carbon atoms, azido, alkylthio groups having from 1 to 6 carbon atoms, alkylsulfinyl groups having from 1 to 6 carbon atoms, alkylsulfonyl groups having from 1 to 6 carbon atoms, 8 9 8 9 groups of formula -NR R and groups of formula -CONR R 8, 89. wherein R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having from 1 to 6 carbon atoms, and Or - R 9 and R 8 together represent a group of the formula - (CH ₂ ) q O _r - (CH ₂ ) _s -, wherein q and s are independently selected from the group consisting of 0 and integers from 1 to 5 and r are 0 or 1 provided that (q + s) <4.5 is an integer of at least 2, and. Ϊ ¹ '. ₍ Groups of Formulas (BI), (B-II), (B-III), (B-IV), (BV), (B-VI), (B-VII), (B-VIII), and (B- IX): 171 (B-4) o .7 173 where and Yippee 1,2 or 3, ·· ’ b Yippee 0, 1 or 2, C Yippee 0. or 1, d Yippee 0,1 or: 2, E Yippee' 0, 1 or 2, f - - ' Yippee 0, Ί or 2, G Yippee 0, 1 or 2, h Yippee 0, 1 or 2, R ²⁰  means atom hydrogen a group of formula -COR where 2 6 R represents an alkyl group having from 1 to 6 carbon atoms or a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of substituents A, A group of the formula -C (= NR) R, wherein X o 17 R and R ^x are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, amino groups, protected amino groups and amino protecting groups, unsubstituted alkyl groups having from 1 to 6 carbon atoms, or substituted alkyl groups , - 174 having from 1 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of substituents D as defined below, R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, hydroxy groups and protected hydroxy groups, 27 ·. R is hydrogen or alkyl having from 1 to 6 carbon atoms, R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having 1 to 6 carbon atoms, amino protecting groups, amino groups, protected amino groups and groups of formula -C (= NR 16) R ^17, wherein R ⁸ and R ? have the above meaning, '30. R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a substituted alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of hydroxy and protected hydroxy groups. R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an amino protecting group, R represents a hydrogen atom, an alkyl group having from 1 28 29 to 6 carbon atoms or a group of the formula-NR 6 R, in which R and R are as defined above, ·. ► E represents an imidazolyl group or a triazolyl group, 175 W represents an aromatic heterocyclic group having from 5 to 8 ring atoms of which from 1 to 4 are nitrogen atoms, said aromatic heterocyclic group being unsubstituted or substituted by at least one alkyl group having from 1 to 6 carbon atoms, 12 3 Q, Q, Q and Q are independently selected from the group consisting of> CH and> N, said substituents selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, amino protecting groups, groups of the formula - C (= NR ^^) R ^^, where _a r ^ -? are as defined above, amino protecting groups, and 18 groups of the formula -CONR 19 R wherein R! 8 and R ³ are independently selected from the group consisting of alkyl groups having 1 to 6 carbon atoms and carboxylic acyl groups, said substituents C are selected from the group consisting of alkyl groups having from From 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, alkoxycarbonyl groups having from 2 to 7 carbon atoms, having the formula -CONR R, where R and R are as defined above, cyano, hydroxy groups and nitro, said substituents D are selected from the group consisting of hydroxy, protected hydroxy, carboxy, protected carboxy, cyano, alkoxy of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, groups of the formula -HNCOR ²³ , - NR ²⁴ r25 2425 2425 -CONR R or -OCONR R wherein «.« KWQ '.λ'. · Ί - '· 176 R> R and R are independently selected from the group consisting of hydrogen atoms and alkyl groups having from 1 to 6 carbon atoms, and pharmaceutically acceptable salts and esters thereof, characterized in that a compound of formula II (Π) is reacted Wherein R, R, R, and X are as defined above, k is 4 1 or 2, and R is: an alkyl group having from 1 to 6 carbon atoms which is unsubstituted or substituted by at least one substituent selected from the group consisting of the substituents E as defined below, an alkenyl group having from 2 to 6 carbon atoms and which is unsubstituted or is at least substituted one substituent selected from the group of the following E substituents, an aryl group as defined above, an aralkyl group in which an alkyl group having from 1 to 6 carbon atoms is substituted with at least one aryl group as defined above, - a cycloalkyl group having from 3 to 7 carbon atoms and which is unsubstituted or substituted by at least one substituent selected from the group consisting of the above-mentioned substituents C, an aromatic heterocyclic group having from 5 to 7 ring atoms in the aromatic ring, at least one said atoms being a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur heteroatoms, said group being unsubstituted or substituted by at least one substituent selected from the above substituent group C, a fused heterocyclic group wherein the aromatic heterocyclic group is as defined above and is fused to an aryl group as defined above or an alkyl group having from 1 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of aromatic heterocyclic groups and fused heterocyclic groups mentioned above and said substituents E are selected from the group consisting of hydroxy, protected hydroxy, amino and protected amino, with a compound of formula III n where C is as defined above, ► and optionally removing any protecting groups, reactions - 178 Wi * - said compound of formula II and said compound of formula III is carried out in the presence of a Group II or III metal salt of the Periodic Table of the Elements. 2. The process according to claim 1, wherein the Group II metal is a Group II metal of the Periodic Table of the Elements. The method of claim 1, wherein the Group III metal is a Group III Group B metal of the Periodic Table of the Elements. The method of claim 1, wherein the metal of Group II or III of the Periodic Table of the Elements is magnesium, aluminum, beryllium, calcium or boron. The method of claim 4, wherein said metal is magnesium, beryllium or calcium. 6. The process of claim 4 wherein said metal is aluminum or boron. 7. The process of claim 4 wherein said metal is magnesium or calcium. 8. The method of claim 4 wherein said metal is aluminum. 4 » 9. The process of claim 4 wherein said metal is magnesium. 10. The process of claim 9 wherein said metal salt is a magnesium bromide / diethyl ether complex, a mixture of said complex with diisopropylethyl 179 amine, 1-ethylpiperidine, or 1,5-diazabicyclo [5.4.0] -5-undecene, bromomagnesium diisopropylamide, bromomagnesiumcyclohexylisopropylamide, bromomagnesium diethylamide or bromomagnesium hexamethyldisilazide, bromomagnesium tert-butoxide, a mixture of lithium diisopropylamide or lithium bistrimethylsilylamide with magnesium bromide and diethyl ether diisodium diisopropyl ether complex, or diethyl ether diisopropyl ether. 11. A process according to claim 1, wherein the compound of formula II and the mercaptan of formula III are used in a molar ratio of from 1 to 1: 1. '™ ..... 12. The process of claim 1 wherein the Group II or III metal salt is present in an amount of from 1 to 20 moles per mole of the compound of Formula II. A process according to claim 1 wherein the salt is a magnesium, aluminum, beryllium, calcium or boron salt, the compound of formula II and the mercaptan of formula III are used in a molar ratio of 1: 1 to 1: 3 and a metal salt of group II or III is present in an amount of from 1 to 20 moles per mole of the compound of formula II. 14. The method of claim 13, wherein said salt is a magnesium bromide / diethyl ether complex, a mixture of said complex with diisopropylethylamine, 1-ethylpiperidine or 1,5-diaza-bicyclo [5.4.0] -5. -undecene, bromagnesiumdiisopropylamide, bromagnesiumcyclohexylisopropylamide, bromagnesiumdiethylamide or bromagnesiumhexamethydisilazide, bromagnesium ether, butoxide> mixture of lithium diisopropylamide or lithiumbistrimethylsilylamide with a magnesium bromide / diethyl ether complex, or diethylaluminum diisopropylamide. 180 15. The method of claim lvyznačující with "et in that R ¹ represents a hydrogen atom, 'and an alkyl radical having from 1 to 6 carbon atoms, $ an aralkyl group, an alkyl group having from 1 to 4 carbon atoms and which is substituted by at least one aryl group, an alkenyl group having from 2 to 6 carbon atoms which is unsubstituted, bold or substituted by one or more halogen atoms, a haloalkyl group having from 1 to 6 carbon atoms, a trisubstituted silylethyl group in which all three or two or one of the substituents are alkyl groups having from 1 to 5 carbon atoms, and ΐ none, one or two of the substituents are aryl groups ¹ , acyloxyalkyl, in which acyl moiety is% an alkanoyl group having from 1 to 6 carbon atoms and an alkyl moiety having from 1 to 6 carbon atoms; an alkoxycarbonyloxyalkyl group in which the alkoxy clay and alkyl moieties each have from 1 to 6 carbon atoms, a cyclic alkoxycarbonyloxyalkyl group in which the t cycloalkyl moiety has from 3 to 7 ring carbon atoms and is unsubstituted or substituted i “i 181 with at least one substituent selected from the group consisting of C and the alkyl moiety has from 1 to 2 6 carbon atoms, (5-alkyl or 5-aryl-2-oxo-1,3-dioxolen-4-yl) methyl group in which the alkyl moiety has from 1 to 4 carbon atoms, or 3-phthalidyl. 16. The method of claim 1, wherein: 2 3. , ... R and R are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms, and groups of the formula Eats where R ³ represents a hydrogen atom or a methyl group, and R ⁸ represents a hydrogen atom, ·. . . A substituted silyl group in which the silyl group has 3 substituents selected from alkyl groups having from 1 to 6 carbon atoms and phenyl groups, 182 an aralkyl group in which the alkyl group having from 1 to 4 carbon atoms is substituted by at least one aryl group, an aralkyloxycarbonyl group in which the aralkyl moiety is as defined above, an alkenyloxycarbonyl group in which the alkenyl group - * X. the moiety has from 2 to 6 carbon atoms and is unsubstituted or substituted by at least one halogen atom, an alkoxycarbonyl group having 2 to 7 carbon atoms, a substituted silylalkoxycarbonyl group in which the alkoxycarbonyl moiety and the substituted silyl moiety are as hereinbefore defined, oxygen containing a heterocyclic group, an alkoxyalkyl group in which the alkoxy and alkyl parts each have from 1 to 6 carbon atoms, 'l ¹ silylalkoxyalkylovou substituted group in which the alkoxyalkyl part and the substituted silyl part has »her hereinbefore defined, ^or! « and · · halogenalkaloyl or alkanoyl of up to 6 carbon atoms, ϊ 2 3 - '6 R ¹ and R together represent a group of formula = C _{(CH3) CH2} OR. 17. The method of claim 1, wherein the method is as follows. . Wherein X is a sulfur atom or a group of the formula> CHR, wherein R represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or an alkoxy group having from 1 to 4 carbon atoms. - 183 The method of claim 1, wherein A is ✓ an alkyl group having from 1 to 4 carbon atoms and which is unsubstituted or is substituted by 1 or 2 substituents selected from the group consisting of a _and the following substituents,, ¾¾ - aryl, as described below, an aralkyl group wherein the alkyl group has from 1 to 3 carbon atoms and is substituted by at least one aryl group below, a heterocyclic group having from 4 to 7 carbon atoms, at least one of which is a heteroatom selected from the group consisting of nitrogen heteroatoms, oxygen and sulfur, said group being unsubstituted or substituted by at least one substituent selected from the group consisting of B ³ substituents on carbon atoms, B ³³ substituents on nitrogen heteroatoms, and T atoms and oxygen atoms to form a sulfinyl or sulfonyl group on sulfur heteroatoms, each as defined below, or an alkyl group having from 1 to 3 carbon atoms and kte Ra is substituted by at least one substituent selected from the group consisting of the above-defined heterocyclic groups · 'Λ · said aryl groups are aromatic carbocyclic groups having 6 to 10 ring carbon atoms and are not _R J is substituted or are substituted by at least one SUBC a substituent selected from the group consisting of defined below 184 substituents C, said substituents A ^and are selected from the group consisting of hydroxy, protected hydroxy, amino, protected amino, -C (= NR ¹⁰ ) NR ¹¹ R ¹² , wherein "10-11". '. , R, R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups and alkyl groups having from 1 to 4 carbon atoms, or R and R together represent a group of formula ^- ( ^{CH 2} ->) _n "/ wherein n is an integer from 2 to 5, or Κ ^Χ θ and 11 ⁿ R together represents a group of formula - (CH -) - wherein p is 2 or 3, and a group of formula -NR ¹³ C (= NR ¹⁴ ) R ¹⁵ wherein 13 14. R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, and alkyl groups having from 1 to 6 carbon atoms, and R ^X1 represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an amino or a protected amino group, or any two of R ^X3 , R ^X4 and R ^X8 together represent a group of the formula - (CH-) - wherein p is 2 or 3, the aforementioned substituents B ^and are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, hydroxy groups, halogen atoms. 185 cyano, nitro, alkoxycarbonyl groups having from 2 to 5 carbon atoms, carboxy groups, oxygen atoms, to form a carbonyl group with a carbon ring atom, ........ ............ ... alkoxyalkyl in which the alkoxy and alkyl moieties both have from 1 to 6 carbon atoms, haloalkyl having from 1 to 6 carbon atoms, <alkanoyloxy groups having from 1 to 6 carbon atoms, ¹ 8 9 8 9 of the formula -NR κ and groups of formula -CONR R, where = ΐ 3 9, R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having from 1 to 4 carbon atoms and 89, or phenyl groups, or R and R together represent a ^? of the formula - (CH_) -O- (CH_) wherein q and c are independently 2 q r 2 s zvol selected from the group consisting of 0 and integers from 1 to 5 and r is 0 or 1, provided that (q + s) is an integer of at least 2, and. š · Δ groups of formulas B1, B-II, B-III, B-IV, BV, B-VI, B-VII, B-VIII and B-IX, said substituents B and ^l are selected from the group consisting of / alkyl groups having from 1 to 4 carbon atoms, amino protecting groups, -C (= NR ³ ) R ¹ , Wherein R and R are as defined above, amino protecting groups and -CONR ^ R ^^ R and R are independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, and benzoyl groups; said substituents ^C are selected from the group consisting of alkyl groups having 1 to 4 carbon atoms, ·, alkoxy groups having 1 to 4 carbon atoms, halogen atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms, 8 9 8 9 groups of the formula -CONR R, wherein R and R are as defined above, cyano, hydroxy and nitro. A method according to claim 1, characterized in. -. „1 t i m, that R means: a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an aralkyl group which is an alkyl group having 1 or 2 carbon atoms and which is substituted by at least one phenyl group, a haloalkyl group having from 1 to 4 carbon atoms, a trisubstituted silylethyl group, wherein all three or two of the substituents are alkyl groups having from 1 to 4 carbon atoms, and none or one of the substituents are phenyl groups, An acyloxyalkyl group in which the acyl moiety is an alkanoyl group having from 2 to 5 carbon atoms and the alkyl moiety has 1 or 2 carbon atoms, an alkoxycarbonyloxyalkyl group in which the alkoxy moiety and the alkyl moiety each have from 1 to 4 carbon atoms, ( 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl group, or 3-phthalidyl. 20. The method of claim 18 wherein 2 3. ,, R 3 and R 3 are independently selected from the group consisting of hydrogen atoms, alkyl groups having from 1 to 4 carbon atoms and groups of the formula wherein R ³ represents a hydrogen atom or a methyl group, and R ³ represents a hydrogen atom, a substituted silyl group in which the silyl group has three substituents selected from alkyl groups having from 1 to 4 carbon atoms and phenyl groups. 188 ι an aralkyl group wherein the alkyl group having from 1 to 4 carbon atoms is substituted with at least one aryl group as defined in claim 18, C 2 -C 7 alkoxycarbonyl, tetrahydropyranyl, 1% alkoxycarbonyl, in which the alkoxy and alkyl moieties each have from 1 to 4 carbon atoms, an alkanoyl or haloalkanoyl group having from 2 to 5 carbon atoms, or 2 3 6 R @ 2 and R @ 2 together represent a group of formula ^ (CH3 JCH3 OR). A process according to claim 18, wherein X is a sulfur atom or a group of formula CHR, wherein _; represents a hydrogen atom, an alkyl group having 1 or 2 'carbon atoms or an alkoxy group having 1 or 2 carbon atoms. 22. The method of claim 18, wherein ³ t in that A represents a alkyl group having 1 or 2 carbon atoms and which is unsubstituted or is substituted by 1 or 5 2 substituents selected from the group consisting of Substituents A below, a phenyl group which is unsubstituted or is substituted by 1 or 2 substituents selected from. pins formed by substituents C? ^The alkyl group in which the alkyl group has from 1 to 3 carbon atoms is substituted by at least one of the groups below. An aryl group which is unsubstituted or is 3 substituted with 1 or 2 substituents selected from below 189 of said C substituents, a heterocyclic group having 5 or 6 ring atoms, from 1 to 3 are heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur heteroatoms, said group being unsubstituted or substituted by at least one substituent; b, selected from the group consisting of substituents B on carbon atoms, substituents B on nitrogen heteroatoms, and oxygen atoms to form a sulfinyl or sulfonyl group on sulfur heteroatoms, all as shown below, said substituents A 1 being selected from the group consisting of hydroxy protected groups hydroxy, amino-protected amino, said B ^u substituents are selected from the group consisting of alkyl groups having 1 or 2 carbon atoms, alkoxy groups having 1 or 2 carbon atoms, hydroxy groups, halogen atoms, cyano groups, nitro groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, carboxy groups, haloalkyl groups having from 1 to 6 carbon atoms, alkanoyloxy groups having from 1 to 6 carbon atoms, 8 9 8 9 -NR R groups and -CONR R groups wherein 8 9 R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having 1 or 2 carbon atoms and 89 phenyl groups, or R and R together are - (CH_) -O- (CH_) - where q and s are not X Q 27 £ S is selected from the group consisting of 0 and integers from 1 to 5 are 0 «or 1, provided that (q + s) is an integer at least 2, and groups of formulas B1, B-II, B-III, B-IV, BV, B-VI, B-VII, B-VIII and B-IX, said B ° substituents being selected from the group consisting of alkyl groups having 1 or 2 atoms carbon, 16 17 amino protecting groups, -C (= NR) R 16 16 wherein R and R, amino protecting groups and -CONR ¹⁸ R ¹⁹ wherein R ^3-8 and R ^3-9 are independently selected from the group consisting of alkyl groups having 1 or 2 carbon atoms, alkyl groups having 2 to 5 carbon atoms, and benzoyl groups, said C * ³ substituents being selected from the group consisting of alkyl groups groups having 1 or 2 carbon atoms, alkoxy groups having 1 or 2 carbon atoms, halogen atoms, -CONR R groups, cyano, hydroxy and nitro groups, A compound of formula IV 191 'where r! represents a hydrogen atom or a carboxyl protecting group, R is a hydrogen atom or a hydroxy protecting group; 42 is an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, a halogen atom, an aryl group as shown below, or an aryloxy group in which aryl part has the meaning given below, Λ -i ί R ' ^w represents a hydrogen atom, an alkyl group having from 1 to 2 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, hydroxy, atomhalogen, cyano, A nitro or -NR R group wherein R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having from 1 to 6 carbon atoms and phenyl groups, or R and R ' together denote a group of formula wherein q and q are independently selected - 192 from the group consisting of 0 and integers from 1 to 5 and r are 0 or 1, provided that (q + s) is an integer of at least 2, R and R are independently selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms and aryl groups as shown below, or R ⁴³ and 46 ¹ R together represent a group of formula - _(CH2) ^ -0 ^ .- _{(CH2) s} ~, é which QAS are independently selected from the group consisting of 0 and integers 1 to 5 and r is 0 or 1, Y represents an oxygen atom or a sulfur atom, and i is 0, 1 or 2, said aryl groups being aromatic carbocyclic groups having from 6 to 14 carbon ring atoms and are unsubstituted or substituted by at least one substituent from the group consisting of substituents C listed below said substituents C are selected from the group consisting of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, halogen atoms, ^alco-? xycarbonyl groups having from 2 to 7 carbon atoms, i QQQQ 4 groups of the formula -CONR R, wherein R and R are as defined above, cyano, hydroxy and nitro, zi ^; And their pharmaceutically acceptable salts and esters. The compound of claim 23, wherein. R ³ means: hydrogen atom, 193 alkyl radical having 1 to 6 carbon atoms, an aralkyl group which is an alkyl radical having 1 to 4 carbon atoms and which is substituted by at least one aryl group as defined in claim 23, and ^x & is an alkenyl group having from 2 to 6 carbon atoms and which is unsubstituted or substituted by one or more halogen atoms, a haloalkyl group having from 1 to 6 carbon atoms; - a trisubstituted silylethyl group in which all three or two or one of the substituents are alkyl groups having from 1 to 5 carbon atoms, and none, one or two of the substituents are aryl groups as set forth in claim 23, an acyloxyalkyl group, wherein the acyl moiety is an alkanoyl group having from 1 to 6 carbon atoms and the alkyl moiety has from 1 to 6 carbon atoms, an alkoxycarbonyl group in which the alkoxy and alkyl moieties each have from 1 to 6 carbon atoms, cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl moiety has from 3 to 7 carbon atoms in the ring and is unsubstituted or is substituted by at least one substituent selected from the group consisting of C, and the alkyl moiety has from 1 to 6 carbon atoms, (5-alkyl or 5-aryl-2-) oxo-1,3-dioxolen-4-yl) methyl in which the alkyl moiety has from 1 - 194 - i up to 4 carbon atoms and the aryl moiety is as defined in claim 23, or 3-phthalidyl. A compound according to claim 23, wherein R ⁴ represents a hydrogen atom - a substituted silyl group in which the silyl group has 3 substituents selected from alkyl groups having from 1 to 6 carbon atoms and phenyl groups, an aralkyl group in which the alkyl group having from 1 to 4 carbon atoms is substituted with at least one aryl group as is described in claim 23, an aralkyloxycarbonyl group in which the aralkyl moiety is as defined above, an alkenyloxycarbonyl group in which the alkenyl moiety has from 2 to 6 carbon atoms and is unsubstituted or substituted by at least one halogen atom, an alkoxycarbonyl group having from 2 to 7 carbon atoms, i a substituted silylalkoxycarbonyl group in which the alkoxycarbonyl moiety and the substituted silyl moiety are as defined above,. an oxygen-containing heterocyclic group; an alkoxyalkyl group in which the alkoxy and alkyl moieties each have from 1 to 6 carbon atoms, A substituted silylalkoxyalkyl group wherein the alkoxy moiety and the substituted silyl moiety are as defined above, or I (% # ''! An alkanoyl or haloalkanoyl group having no more than 6 carbon atoms. '. A compound according to claim 23, wherein R is an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a "halogen atom / aryl group as below," or an aryloxy group in which the aryl moiety is as defined below, said aryl groups being aromatic carbocyclic groups having from 6 to 10 carbon atoms in the ring and are unsubstituted or substituted by at least one substituent selected from the group consisting of substituents C ^and , below, said substituents G ^and are selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms, the group -CONR R, wherein R and R are are as defined above, cyano, hydroxy and nitro. A compound according to claim 25, wherein R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen, cyano, nitro or a group of the formula -NR R wherein R and R independently represent hydrogen, an amino protecting group, * alkyl of l to 4 carbon atoms, 8 9, or phenyl, or R and R together form a group - _(CH2) ^ - O _r - ( CH ₂ ) _s -, wherein q and s are independently t or all numbers 1 to 5 and r are 0 or 1, provided that the sum of q + s is at least 2. 195a A compound independently selected from pins having from 1 to are as claimed in claim 23, wherein R ⁴⁵ and R ⁴⁶ are groups consisting of alkyl groups of carbon atoms and aryl groups, such as R 25 and R ¹¹ and R 10. of a sol is a group of formula - <= ^E 2> _q - ^C r - < ^CH 2 '-' ^k '< »1 q and s are independently selected from the group consisting of · 0 and integers from 1 to -5 and r is 0 or 1. -AND 196 The compound of claim 23, wherein: a hydrogen atom, an X alkyl group having from 1 to 4 carbon atoms, an aralkyl group which is an alkyl group having X1. Given 1 or 2 carbon atoms and which is substituted by at least one phenyl group, a haloalkyl group having from 1 to 4 carbon atoms, a trisubstituted silylethyl group in which all three or two of the substituents are alkyl groups having from 1 to 4 carbon atoms, and none or one of the substituents is phenyl groups, an acyloxyalkyl group in which the acyl moiety is an alkanoyl group having from 2 to 5 carbon atoms and the alkyl moiety has 1 or 2 atoms carbon • 4 • 7 $ 1 'i an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl moieties each have from 1 to 4 carbon atoms, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, or 3-phthalidyl. A compound according to claim 25, wherein R ^43- is a hydrogen atom, a substituted silyl group in which the silyl group is a hydrogen atom. 197 has three substituents selected from alkyl groups having from 1 to 4 carbon atoms and phenyl groups, and an aralkyl group in which an alkyl group having 1 or 2 carbon atoms is substituted with at least one aryl group, as set forth in claim 25, an aralkyloxycarbonyl group wherein the aralkyl moiety r is as defined above, an alkoxycarbonyl group having from 2 to 5 carbon atoms, a tetrahydropyranyl group, an alkoxyalkyl group wherein the alkoxy and alkyl moieties each have from 1 to 5 carbon atoms; Or alkanoyl or haloalkanoyl having from 2 to 5 carbon atoms. A compound according to claim 25, wherein R is an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a halogen atom, a phenyl group or a phenoxy group. & · A compound according to claim 25, wherein R is hydrogen, alkyl having 1 or 2 carbon atoms an alkoxy group having 1 or 2 carbon atoms, a hydroxy group, a halogen atom, a cyano group, a nitro group or a group of the formula -NR R wherein R and R are independently selected from the group consisting of hydrogen atoms, amino protecting groups, alkyl groups having 1 or 2 carbon atoms benzoyloxycarbonyl and phenyl, or R and ^R together represent a group of formula i -Ψ - 198 - (CH ₂ ) q "O _r - (CH ₂ ) _g -, wherein q and are independently selected from the group consisting of 0 and integers from 1 to 5 and r is 0 or 1, provided that (q + s) is an integer number at least 2. . ,. '45 46 A compound according to claim 25, wherein R and R are independently selected from the group consisting of alkyl groups having 1 or 2 carbon atoms and phenyl groups, or R ⁴³ and R ⁴ together represent a group of the formula ^wherein . '· "....... '" q and s "are independently selected from the group consisting of 0 and integers from 1 to 5 and r is 0 or 1. The compound of claim 23, 4-nitrobenzyl 2- (2-diethylcarbamoylphenylthio) -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate. > and The compound of claim 23, 4-nitrobenzyl 2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate. 1 The compound of claim 23, 4-nitrobenzyl-2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- (1-trimethyl) -1,3-silyloxyethyl) -1-carbapen-2-em-3-carboxylate. ξ A compound according to claim 23, 4-nitrobenzyl 2- (2-diethylcarbamoylphenylthio) -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate, AND A compound according to claim 23, 4-nitrobenzyl 2- (2-diethylcarbamoylphenylsulfinyl) -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate. The compound of claim 23, 4-nitrobenzyl 2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate. - 199 'i •''and \. · ^: 3 ·%, Ύ''i A compound according to claim 23, 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylthio] -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate. A compound according to claim 23, 4-nitrobenzyl-2- [2- (1-perhydroazepinylcarbonyl) phenylsulfinyl] -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate. | (>: Ř The compound of claim 23, 4-nitrobenzyl 2- [2- (1-perhydrazazinylcarbonyl) phenylsulfonyl] -1-methyl-6- (1-trimethylsilyloxyethyl) -1-carbapen-2-em-3-carboxylate. A compound according to claim 23, 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylthio] -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate. The compound of claim 23, 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylsulfinyl] -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate. A compound according to claim 23, 4-nitrobenzyl 2- [2- (1-perhydroazepinylcarbonyl) phenylsulfonyl] -1-methyl-6- (1-hydroxyethyl) -1-carbapen-2-em-3-carboxylate.